Human plasma kallikrein inhibitors

ABSTRACT

Disclosed are compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also disclosed are pharmaceutical compositions comprising at least one such compound, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 61/949,808, filed Mar. 7, 2014; and U.S.Provisional Patent Application Ser. No. 61/981,515, filed Apr. 18, 2014.

BACKGROUND

Serine proteases make up the largest and most extensively studied groupof proteolytic enzymes. Their critical roles in physiological processesextend over such diverse areas as blood coagulation, fibrinolysis,complement activation, reproduction, digestion, and the release ofphysiologically active peptides. Many of these vital processes beginwith cleavage of a single peptide bond or a few peptide bonds inprecursor protein or peptides. Sequential limited proteolytic reactionsor cascades are involved in blood clotting, fibrinolysis, and complementactivation. The biological signals to start these cascades can becontrolled and amplified as well. Similarly, controlled proteolysis canshut down or inactivate proteins or peptides through single bondcleavages.

Kallikreins are a subgroup of serine proteases. In humans, plasmakallikrein (KLKB1) has no known homologue, while tissuekallikrein-related peptidases (KLKs) encode a family of fifteen closelyrelated serine proteases. Plasma kallikrein participates in a number ofpathways relating to the intrinsic pathway of coagulation, inflammation,and the complement system.

Coagulation is the process by which blood forms clots, for example tostop bleeding. The physiology of coagulation is somewhat complex insofaras it includes two separate initial pathways, which converge into afinal common pathway leading to clot formation. In the final commonpathway, prothrombin is converted into thrombin, which in turn convertsfibrinogen into fibrin, the latter being the principal building block ofcross-linked fibrin polymers which form a hemostatic plug. Of the twoinitial pathways upstream of the final common pathway, one is known asthe contact activation or intrinsic pathway, and the other is known asthe tissue factor or extrinsic pathway.

The intrinsic pathway begins with formation of a primary complex oncollagen by high-molecular-weight kininogen (HMWK), prekallikrein, andFXII (Factor XII; Hageman factor). Prekallikrein is converted tokallikrein, and FXII is activated to become FXIIa. FXIIa then convertsFactor XI (FXI) into FXIa, and FXIa in turn activates Factor IX (FIX),which with its co-factor FVIIIa form the “tenase” complex, whichactivates Factor X (FX) to FXa. It is FXa which is responsible for theconversion of prothrombin into thrombin within the final common pathway.

Prekallikrein, the inactive precursor of plasma kallikrein, issynthesized in the liver and circulates in the plasma bound to HMWK oras a free zymogen. Prekallikrein is cleaved by activated factor XII(FXIIa) to release activated plasma kallikrein (PK). Activated plasmakallikrein displays endopeptidase activity towards peptide bonds afterarginine (preferred) and lysine. PK then generates additional FXIIa in afeedback loop which in turn activates factor XI (FXI) to FXIa to connectto the common pathway. Although the initial activation of the intrinsicpathway is through a small amount of FXIIa activating a small amount ofPK, it is the subsequent feedback activation of FXII by PK that controlsthe extent of activation of the intrinsic pathway and hence downstreamcoagulation. Hathaway, W. E., et al. (1965) Blood 26:521-32.

Activated plasma kallikrein also cleaves HMWK to release the potentvasodilator peptide bradykinin. It is also able to cleave a number ofinactive precursor proteins to generate active products, such as plasmin(from plasminogen) and urokinase (from prourokinase). Plasmin, aregulator of coagulation, proteolytically cleaves fibrin into fibrindegradation products that inhibit excessive fibrin formation.

Patients who have suffered acute myocardial infarction (MI) showclinical evidence of being in a hypercoagulable (clot-promoting) state.This hypercoagulability is paradoxically additionally aggravated inthose receiving fibrinolytic therapy. Increased generation of thrombin,as measured by thrombin-antithrombin III (TAT) levels, is observed inpatients undergoing such treatment compared to the already high levelsobserved in those receiving heparin alone. Hoffmeister, H. M. et al.(1998) Circulation 98:2527-33. The increase in thrombin has beenproposed to result from plasmin-mediated activation of the intrinsicpathway by direct activation of FXII by plasmin.

Not only does the fibrinolysis-induced hypercoagulability lead toincreased rates of reocclusion, but it is also probably responsible, atleast in part, for failure to achieve complete fibrinolysis of the clot(thrombus), a major shortcoming of fibrinolytic therapy (Keeley, E. C.et al. (2003) Lancet 361: 13-20). Another problem in fibrinolytictherapy is the accompanying elevated risk of intracranial hemorrhage.Menon, V. et al. (2004) Chest 126:549S-575S; Fibrinolytic TherapyTrialists' Collaborative Group (1994) Lancet 343:311-22. Hence, anadjunctive anti-coagulant therapy that does not increase the risk ofbleeding, but inhibits the formation of new thrombin, would be greatlybeneficial.

Therefore, a need exists to develop inhibitors of PK that can tip thebalance of fibrinolysis/thrombosis at the occluding thrombus towarddissolution, thereby promoting reperfusion and also attenuating thehypercoagulable state, thus preventing thrombus from reforming andreoccluding the vessel.

SUMMARY OF THE INVENTION

Provided are compounds, pharmaceutical compositions comprising thecompounds, and methods useful for inhibiting plasma kallikrein andtreating or preventing plasma kallikrein-related diseases andconditions. The compounds and their pharmaceutically acceptable saltsare specifically useful as inhibitors of human plasma kallikrein.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula I:

-   -   wherein:    -   V is optionally substituted aryl or heteroaryl;    -   W is optionally substituted aryl or heteroaryl;    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), —C(NH₂),        —C(NR^(a)R^(b)), —C(N₃), —C(CN), —C(NO₂), —C(S(O)_(n)R^(a)),        —C[—C(═O)R^(c)], —C[—C(═O)R^(c)], —C[—C(═O)NR^(c)R^(d)],        —C[—C(═O)SR^(c)], —C[—S(O)R^(c)], —C[—S(O)₂R^(c)],        —C[S(O)(OR^(c))], —C[—S(O)₂(OR^(c))], —C[—SO₂NR^(c)R^(d)],        —C(halogen), —C[(C₁-C₈)alkyl], —C[(C₄-C₈)carbocyclylalkyl],        —C[(C₁-C₈)substituted alkyl], —C[(C₂-C₈)alkenyl],        —C[(C₂-C₈)substituted alkenyl], —C[(C₂-C₈)alkynyl],        —C[(C₂-C₈)substituted alkynyl], —C[aryl(C₁-C₈)alkyl], C(O)N,        CH₂N, N, C(O), P(O), —O—, S(O)N, or S(O)₂N; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH), C(O(C₁-C₆)alkyl), —C(NH₂),            —C(NR^(a)R^(b)), —C(N₃), —C(CN), —C(NO₂), —C(S(O)_(n)R^(a)),            —C[—C(═O)R^(c)], —C[—C(═O)R^(c)], —C[—C(═O)NR^(c)R^(d)],            —C[—C(═O)SR^(c)], —C[—S(O)R^(c)], —C[—S(O)₂R^(c)],            —C[S(O)(OR^(c))], —C[—S(O)₂(OR^(c))], —C[—SO₂NR^(c)R^(d)],            —C(halogen), —C[(C₁-C₈)alkyl], —C[(C₄-C₈)carbocyclylalkyl],            —C[(C₁-C₈)substituted alkyl], —C[(C₂-C₈)alkenyl],            —C[(C₂-C₈)substituted alkenyl], —C[(C₂-C₈)alkynyl],            —C[(C₂-C₈)substituted alkynyl], or —C[aryl(C₁-C₈)alkyl],            then —Y—R⁴ is present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents one or more substituents independently        selected from the group consisting of halo, hydroxy,        (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino,        amino(C₁-C₆)alkyl, —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂NH₂, (C₃-C₈)cycloalkyl, (CH₂)_(r)OR^(a),        NO₂, (CH₂)_(r)NR^(a)R^(b), (CH₂)_(r)C(O)R^(a), NR^(a)C(O)R^(b),        C(O)NR^(c)R^(d), NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),        NHC(═NR^(a))NR^(c)R^(d), NR^(a)R^(b), SO₂NR^(c)R^(d),        NR^(a)SO₂NR^(c)R^(d), NR^(a)SO₂—(C₁-C₆)alkyl, NR^(a)SO₂R^(a),        S(O)_(p)R^(a), (CF₂)_(r)CF₃, NHCH₂R^(a), OCH₂R^(a), SCH₂R^(a),        NH(CH₂)₂(CH₂)_(r)R^(a), O(CH₂)₂(CH₂)_(r)R^(a), and        S(CH₂)₂(CH₂)_(r)R^(a); or    -   alternatively Z is a 5- or 6-membered aromatic heterocycle        containing from 1 to 4 heteroatoms selected from the group        consisting of N, O, and S;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —C(═NH)NH₂, —CONR^(a)R^(b), —(C₁-C₆)alkylCONR^(a)R^(b), —SO₂CH₃,        formyl, acyl, —NH₂, —C(═NH)NH(OH),        —C(═NH)NH(C(O)O—(C₁-C₆)alkyl),        —C(═NH)NH(C(O)O—(C₁-C₆)haloalkyl),        —C(═NH)NH(C(O)S—(C₁-C₆)alkyl),        —C(═NH)NH(C(O)(OCH(C₁-C₆)alkyl)OC(O)(C₁-C₆)alkyl), optionally        substituted aryl, or optionally substituted heteroaryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        (C₃-C₈)cycloalkyl, (CH₂)_(r)OR^(a), NO₂, (CH₂)_(r)NR^(a)R^(b),        (CH₂)_(r)C(O)R^(a), NR^(a)C(O)R^(b), C(O)NR^(c)R^(d),        NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),        NHC(═NR^(a))NR^(c)R^(d), NR^(a)R^(b) SO₂NR^(c)R^(d),        NR^(a)SO₂NR^(c)R^(d), NR^(a)SO₂—(C₁-C₆)alkyl, NR^(a)SO₂R^(a),        S(O)_(p)R^(a), (CF₂)_(r)CF₃, NHCH₂R^(a), OCH₂R^(a), SCH₂R^(a),        NH(CH₂)₂(CH₂)_(r)R^(a), O(CH₂)₂(CH₂)_(r)R^(a), or        S(CH₂)₂(CH₂)_(r)R^(a); or alternatively R^(3a) is a 5- or        6-membered aromatic heterocycle containing from 1 to 4        heteroatoms selected from the group consisting of N, O, and S;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or        —(CR^(a)R^(b))_(r)(CR^(a)R^(b))_(p)— fused to the 4-position of        the ring bearing Z to form a 5- to 7-membered heterocyclic ring        with optional substituents; or, when R³ is phenyl, can represent        —NR^(a)— fused to the position ortho to X on that phenyl;    -   each R^(a) and R^(b) is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl,        (C₃-C₈)carbocyclylalkyl, —C(═O)R^(c), —C(═O)OR^(c),        —C(═O)NR^(c)R^(d), —C(═O)SR^(c), S(O)R^(c), —S(O)₂R^(c),        —S(O)(OR^(c)), or —SO₂NR^(c)R^(d);    -   each R^(c) and R^(d) is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₄-C₈) carbocyclylalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl, or aryl(C₁-C₈)alkyl;        or when R and R^(d) are bonded to a common nitrogen atom, then        they may form a 3- to 7-membered heterocyclic ring wherein        optionally a carbon atom of said heterocyclic ring may be        replaced with —O—, —S— or —NR^(a)—;

can represent

-   -   n is 2 or 3;    -   r is independently for each occurrence 0, 1, 2, or 3;    -   p is independently for each occurrence 0, 1, or 2; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, the compound is represented by formula II:

In certain embodiments, the compound is represented by formula III:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula IV:

In certain embodiments, the compound is represented by formula V:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula VI:

In certain embodiments, the compound is represented by formula VII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula VIII:

In certain embodiments, the compound is represented by formula IX:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula X:

In certain embodiments, the compound is represented by formula XI:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XII:

In certain embodiments, the compound is represented by formula XIII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XIV:

In certain embodiments, the compound is represented by formula XV:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XVI:

In certain embodiments, the compound is represented by formula XVII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl; and    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, the compound is represented by formula XVIII:

In certain embodiments, the compound is represented by formula XIX:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl; and    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XX:

In certain embodiments, the compound is represented by formula XXI:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl; and    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XXII:

In certain embodiments, the compound is represented by formula XXIII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl; and    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In certain embodiments, the compound is represented by formula XXIV:

In certain embodiments, the compound is represented by formula XXV:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl; and

can represent

In other embodiments, the compound is represented by formula XXVI:

wherein:

-   -   X represents CH, C(OH), —C(NH₂), or —C(NR^(a)R^(b));    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, —NH₂, or optionally substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂; and    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl.

In certain aspects, the invention provides a pharmaceutical composition,comprising a compound of the invention, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides a method of treating orpreventing a disease or condition characterized by unwanted plasmakallikrein activity. The method comprises the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, therebytreating or preventing the disease or condition characterized byunwanted plasma kallikrein activity. In one embodiment, the disease orcondition characterized by unwanted plasma kallikrein activity isselected from the group consisting of stroke, inflammation, reperfusioninjury, acute myocardial infarction, deep vein thrombosis, postfibrinolytic treatment condition, angina, edema, angioedema, hereditaryangioedema, sepsis, arthritis, hemorrhage, blood loss duringcardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus,retinopathy, diabetic retinopathy, diabetic macular edema, diabeticmacular degeneration, age-related macular edema, age-related maculardegeneration, proliferative retinopathy, neuropathy, hypertension, brainedema, increased albumin excretion, macroalbuminuria, and nephropathy.

DETAILED DESCRIPTION

Inhibitors of plasma kallikrein have been reported and are useful intherapeutic methods and compositions suitable for use in eliminating orreducing various forms of ischemia, including but not limited toperioperative blood loss, cerebral ischemia, the onset of systemicinflammatory response, and/or reperfusion injury, e.g., reperfusioninjury associated with cerebral ischemia or a focal brain ischemia.Perioperative blood loss results from invasive surgical procedures thatlead to contact activation of complement components and thecoagulation/fibrinolysis systems.

Kallikrein inhibitors can be used to reduce or prevent perioperativeblood loss and a systemic inflammatory response in patients subjected toinvasive surgical procedures, especially cardiothoracic surgeries.Kallikrein inhibitors can also be used to reduce or prevent cerebralischemia and stroke, and/or reperfusion injury associated with cerebralischemia. They can also prevent neurological and cognitive deficitsassociated with stroke, blood loss, and cerebral ischemia, e.g., eventsthat are not associated with surgical intervention. Further examples ofapplications for kallikrein inhibitors include pediatric cardiacsurgery, lung transplantation, total hip replacement, and orthotopicliver transplantation, to reduce or prevent stroke during theseprocedures, as well as to reduce or prevent stroke during coronaryartery bypass grafting (CABG) and extracorporeal membrane oxygenation(ECMO).

Definitions

The term “alkyl” as used herein is a term of art and refers to saturatedaliphatic groups, including straight-chain alkyl groups, branched-chainalkyl groups, cycloalkyl (alicyclic) groups, alkyl substitutedcycloalkyl groups, and cycloalkyl substituted alkyl groups. In certainembodiments, a straight-chain or branched-chain alkyl has about 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain,C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer. In oneembodiment, the term “alkyl” refers to a C₁-C₁₀ straight-chain alkylgroup. In one embodiment, the term “alkyl” refers to a C₁-C₆straight-chain alkyl group. In one embodiment, the term “alkyl” refersto a C₃-C₁₂ branched-chain alkyl group. In one embodiment, the term“alkyl” refers to a C₃-C₈ branched-chain alkyl group. Cycloalkyls havefrom about 3 to about 10 carbon atoms in their ring structure, andalternatively about 5, 6, or 7 carbons in the ring structure.

The term “heterocyclyl” as used herein refers to a radical of anon-aromatic ring system, including, but not limited to, monocyclic,bicyclic, and tricyclic rings, which can be completely saturated orwhich can contain one or more units of unsaturation, for the avoidanceof doubt, the degree of unsaturation does not result in an aromatic ringsystem, and having 3 to 12 atoms including at least one heteroatom, suchas nitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention, thefollowing are examples of heterocyclic rings: aziridinyl, azirinyl,oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, azetyl,oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl,dioxetenyl, dithietanyl, dithietyl, furyl, dioxalanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl,benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl,benzoxadiazolyl, benzthiadiazolyl, indolyl, benztriazolyl,naphthyridinyl, azepines, azetidinyl, morpholinyl, oxopiperidinyl,oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl,thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

The term “heteroatom” is art-recognized, and includes an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium, andalternatively oxygen, nitrogen or sulfur.

The term “cycloalkylalkyl” as used herein refers to an alkyl groupsubstituted with one or more cycloalkyl groups.

The term “heterocycloalkylalkyl” as used herein refers to an alkyl groupsubstituted with one or more heterocycloalkyl (i.e., heterocyclyl)groups.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond. Representative examples ofalkynyl include, but are not limited, to acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkylene” is art-recognized, and as used herein pertains to adiradical obtained by removing two hydrogen atoms of an alkyl group, asdefined above. In one embodiment an alkylene refers to a disubstitutedalkane, i.e., an alkane substituted at two positions with substituentssuch as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, orthe like. That is, in one embodiment, a “substituted alkyl” is an“alkylene”.

The term “amino” is a term of art and as used herein refers to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R_(a), R_(b), and R_(c) each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(x)—R_(d), or R_(a) and R_(b), takentogether with the N atom to which they are attached complete aheterocycle having from 4 to 8 atoms in the ring structure; R_(d)represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or apolycyclyl; and x is zero or an integer in the range of 1 to 8. Incertain embodiments, only one of R_(a) or R_(b) may be a carbonyl, e.g.,R_(a), R_(b), and the nitrogen together do not form an imide. In otherembodiments, R_(a) and R_(b) (and optionally R_(c)) each independentlyrepresent a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(x)—R_(d). In oneembodiment, the term “amino” refers to —NH₂.

The term “acyl” is a term of art and as used herein refers to any groupor radical of the form RCO— where R is any organic group, e.g., alkyl,aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groupsinclude acetyl, benzoyl, and malonyl.

The term “aminoalkyl” as used herein refers to an alkyl groupsubstituted with one or more one amino groups. In one embodiment, theterm “aminoalkyl” refers to an aminomethyl group.

The term “aminoacyl” is a term of art and as used herein refers to anacyl group substituted with one or more amino groups.

The term “aminothionyl” as used herein refers to an analog of anaminoacyl in which the O of RC(O)— has been replaced by sulfur, hence isof the form RC(S)—.

The term “phosphoryl” is a term of art and as used herein may in generalbe represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl; for example, —P(O)(OMe)- or —P(O)(OH)₂. When used tosubstitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkylmay be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N; for example, —O—P(O)(OH)OMe or —NH—P(O)(OH)₂. WhenQ50 is S, the phosphoryl moiety is a “phosphorothioate.”

The term “aminophosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one amino group, as defined herein; forexample, —P(O)(OH)NMe₂.

The term “carbonyl” as used herein refers to —C(O)—.

The term “thiocarbonyl” as used herein refers to —C(S)—.

The term “alkylphosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one alkyl group, as defined herein; forexample, —P(O)(OH)Me.

The term “alkylthio” as used herein refers to alkyl-S—.

The term “aryl” is a term of art and as used herein refers to includesmonocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, forexample, benzene, naphthalene, anthracene, and pyrene. The aromatic ringmay be substituted at one or more ring positions with one or moresubstituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromaticor heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano,or the like. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings (the rings are “fused rings”) wherein at leastone of the rings is an aromatic hydrocarbon, e.g., the other cyclicrings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls. In one embodiment, the term “aryl”refers to a phenyl group.

The term “heteroaryl” is a term of art and as used herein refers to amonocyclic, bicyclic, and polycyclic aromatic group having one or moreheteroatoms in the ring structure, for example, pyrrole, furan,thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,pyrazine, pyridazine and pyrimidine, and the like. The “heteroaryl” maybe substituted at one or more ring positions with one or moresubstituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromaticor heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano,or the like. The term “heteroaryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings (the rings are “fused rings”) wherein at leastone of the rings is an aromatic group having one or more heteroatoms inthe ring structure, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

The term “aralkyl” or “arylalkyl” is a term of art and as used hereinrefers to an alkyl group substituted with an aryl group.

The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and asused herein refers to an alkyl group substituted with a heteroarylgroup.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “aryloxy” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroaryloxy” as used herein means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

The term “carbocyclyl” as used herein means a monocyclic or multicyclic(e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3to 12 carbon atoms that is completely saturated or has one or moreunsaturated bonds, and for the avoidance of doubt, the degree ofunsaturation does not result in an aromatic ring system (e.g., phenyl).Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl,2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and2-cyclopentenylmethyl.

The term “cyano” is a term of art and as used herein refers to —CN.

The term “fluoroalkyl” as used herein refers to an alkyl group, asdefined herein, wherein some or all of the hydrogens are replaced withfluorines.

The term “halo” is a term of art and as used herein refers to —F, —Cl,—Br, or —I.

The term “hydroxy” is a term of art and as used herein refers to —OH.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,compounds of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,fragmentation, decomposition, cyclization, elimination, or otherreaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

For purposes of the invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemistry terms herein are used according to conventional usage inthe art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms(ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated hereinby reference). Unless otherwise defined, all technical and scientificterms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention pertains.

The term “pharmaceutically acceptable salt” as used herein includessalts derived from inorganic or organic acids including, for example,hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric,formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic,salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and otheracids. Pharmaceutically acceptable salt forms can include forms whereinthe ratio of molecules comprising the salt is not 1:1. For example, thesalt may comprise more than one inorganic or organic acid molecule permolecule of base, such as two hydrochloric acid molecules per moleculeof compound of Formula I. As another example, the salt may comprise lessthan one inorganic or organic acid molecule per molecule of base, suchas two molecules of compound of Formula I per molecule of tartaric acid.

The terms “carrier” and “pharmaceutically acceptable carrier” as usedherein refer to a diluent, adjuvant, excipient, or vehicle with which acompound is administered or formulated for administration. Non-limitingexamples of such pharmaceutically acceptable carriers include liquids,such as water, saline, and oils; and solids, such as gum acacia,gelatin, starch paste, talc, keratin, colloidal silica, urea, and thelike. In addition, auxiliary, stabilizing, thickening, lubricating,flavoring, and coloring agents may be used. Other examples of suitablepharmaceutical carriers are described in Remington's PharmaceuticalSciences by E. W. Martin, herein incorporated by reference in itsentirety.

The term “treat” as used herein means prevent, halt or slow theprogression of, or eliminate a disease or condition in a subject. In oneembodiment “treat” means halt or slow the progression of, or eliminate adisease or condition in a subject. In one embodiment, “treat” meansreduce at least one objective manifestation of a disease or condition ina subject.

The term “effective amount” as used herein refers to an amount that issufficient to bring about a desired biological effect.

The term “therapeutically effective amount” as used herein refers to anamount that is sufficient to bring about a desired therapeutic effect.

The term “inhibit” as used herein means decrease by an objectivelymeasurable amount or extent. In various embodiments “inhibit” meansdecrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95percent compared to relevant control. In one embodiment “inhibit” meansdecrease 100 percent, i.e., halt or eliminate.

The term “subject” as used herein refers to a mammal. In variousembodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep,horse, cow, or non-human primate. In one embodiment, a subject is ahuman.

Compounds

In some aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula I:

-   -   wherein:    -   V is optionally substituted aryl or heteroaryl;    -   W is optionally substituted aryl or heteroaryl;    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), —C(NH₂),        —C(NR^(a)R^(b)), —C(N₃), —C(CN), —C(NO₂), —C(S(O)_(n)R^(a)),        —C[—C(═O)R^(c)], —C[—C(═O)R^(c)], —C[—C(═O)NR^(c)R^(d)],        —C[—C(═O)SR^(c)], —C[—S(O)R^(c)], —C[—S(O)₂R^(c)],        —C[S(O)(OR^(c))], —C[—S(O)₂(OR^(c))], —C[—SO₂NR^(c)R^(d)],        —C(halogen), —C[(C₁-C₈)alkyl], —C[(C₄-C₈)carbocyclylalkyl],        —C[(C₁-C₈)substituted alkyl], —C[(C₂-C₈)alkenyl],        —C[(C₂-C₈)substituted alkenyl], —C[(C₂-C₈)alkynyl],        —C[(C₂-C₈)substituted alkynyl], —C[aryl(C₁-C₈)alkyl], C(O)N,        CH₂N, N, C(O), P(O), —O—, S(O)N, or S(O)₂N; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH), C(O(C₁-C₆)alkyl), —C(NH₂),            —C(NR^(a)R^(b)), —C(N₃), —C(CN), —C(NO₂), —C(S(O)_(n)R^(a)),            —C[—C(═O)R^(c)], —C[—C(═O)R^(c)], —C[—C(═O)NR^(c)R^(d)],            —C[—C(═O)SR^(c)], —C[—S(O)R^(c)], —C[—S(O)₂R^(c)],            —C[S(O)(OR^(c))], —C[—S(O)₂(OR^(c))], —C[—SO₂NR^(c)R^(d)],            —C(halogen), —C[(C₁-C₈)alkyl], —C[(C₄-C₈)carbocyclylalkyl],            —C[(C₁-C₈)substituted alkyl], —C[(C₂-C₈)alkenyl],            —C[(C₂-C₈)substituted alkenyl], —C[(C₂-C₈)alkynyl],            —C[(C₂-C₈)substituted alkynyl], or —C[aryl(C₁-C₈)alkyl],            then —Y—R⁴ is present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents one or more substituents independently        selected from the group consisting of halo, hydroxy,        (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino,        amino(C₁-C₆)alkyl, —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂NH₂, (C₃-C₈)cycloalkyl, (CH₂)_(r)OR^(a),        NO₂, (CH₂)_(r)NR^(a)R^(b), (CH₂)_(r)C(O)R^(a), NR^(a)C(O)R^(b)        C(O)NR^(c)R^(d), NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),        NHC(═NR^(a))NR^(c)R^(d), NR^(a)R^(b), SO₂NR^(c)R^(d),        NR^(a)SO₂NR^(c)R^(d), NR^(a)SO₂—(C₁-C₆)alkyl, NR^(a)SO₂R^(a),        S(O)_(p)R^(a), (CF₂)_(r)CF₃, NHCH₂R^(a), OCH₂R^(a), SCH₂R^(a),        NH(CH₂)₂(CH₂)_(r)R^(a), O(CH₂)₂(CH₂)_(r)R^(a), and        S(CH₂)₂(CH₂)_(r)R^(a); or alternatively Z is a 5- or 6-membered        aromatic heterocycle containing from 1 to 4 heteroatoms selected        from the group consisting of N, O, and S;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —C(═NH)NH₂, —CONR^(a)R^(b), —(C₁-C₆)alkylCONR^(a)R^(b), —SO₂CH₃,        formyl, acyl, —NH₂, —C(═NH)NH(OH),        —C(═NH)NH(C(O)O—(C₁-C₆)alkyl),        —C(═NH)NH(C(O)O—(C₁-C₆)haloalkyl),        —C(═NH)NH(C(O)S—(C₁-C₆)alkyl),        —C(═NH)NH(C(O)(OCH(C₁-C₆)alkyl)OC(O)(C₁-C₆)alkyl), optionally        substituted aryl, or optionally substituted heteroaryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        (C₃-C₈)cycloalkyl, (CH₂)_(r)OR^(a), NO₂, (CH₂)_(r) NR^(a)R^(b),        (CH₂)_(r)C(O)R^(a), NR^(a)C(O)R^(b), C(O)NR^(c)R^(d),        NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),        NHC(═NR^(a))NR^(c)R^(d), NR^(a)R^(b) SO₂NR^(c)R^(d),        NR^(a)SO₂NR^(c)R^(d), NR^(a)SO₂—(C₁-C₆)alkyl, NR^(a)SO₂R^(a),        S(O)_(p)R^(a), (CF₂)_(r)CF₃, NHCH₂R^(a), OCH₂R^(a), SCH₂R^(a),        NH(CH₂)₂(CH₂)_(r)R^(a), O(CH₂)₂(CH₂)_(r)R^(a), or        S(CH₂)₂(CH₂)_(r)R^(a); or alternatively R^(3a) is a 5- or        6-membered aromatic heterocycle containing from 1 to 4        heteroatoms selected from the group consisting of N, O, and S;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or        —(CR^(a)R^(b))_(r)(CR^(a)R^(b))_(p)— fused to the 4-position of        the ring bearing Z to form a 5- to 7-membered heterocyclic ring        with optional substituents; or, when R³ is phenyl, can represent        —NR^(a)— fused to the position ortho to X on that phenyl;    -   each R^(a) and R^(b) is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl,        (C₃-C₈)carbocyclylalkyl, —C(═O)R^(c), —C(═O)OR^(c),        —C(═O)NR^(c)R^(d), —C(═O)SR^(c), S(O)R^(c), —S(O)₂R^(c),        —S(O)(OR^(c)), or —SO₂NR^(c)R^(d);    -   each R^(c) and R^(d) is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₄-C₈) carbocyclylalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl, or aryl(C₁-C₈)alkyl;        or when R and R^(d) are bonded to a common nitrogen atom, then        they may form a 3- to 7-membered heterocyclic ring wherein        optionally a carbon atom of said heterocyclic ring may be        replaced with —O—, —S— or —NR^(a)—;

can represent

-   -   n is 2 or 3;    -   r is independently for each occurrence 0, 1, 2, or 3;    -   p is independently for each occurrence 0, 1, or 2; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In certain embodiments, R³ represents phenylene-R^(3a).

In certain embodiments, —R³—R^(3a) represents

In certain embodiments, —R³—R^(3a) represents

In certain embodiments, —R³—R^(3a) represents

In certain embodiments, R^(3a) is absent.

In certain embodiments, R⁴ is cyclopropyl.

In certain embodiments, R³ is phenyl, and R^(3a) is ortho, meta, or para—OH.

In certain embodiments, R³ is phenyl, and R^(3a) is meta or para —NH₂.

In certain embodiments, R³ is phenyl, and R^(3a) is meta or para —CN.

In certain embodiments, Z is absent.

In certain embodiments, Z represents fluoro.

In certain embodiments, Z represents chloro.

In certain embodiments, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In certain embodiments, Z represents 6-F.

In certain embodiments, R^(1c) represents aminomethyl.

In certain embodiments, R^(1c) represents cyano.

In certain embodiments, R^(1c) represents —SO₂CH₃.

In certain embodiments, wherein R² is —CH₃ or —CF₃.

In certain embodiments, R² is —CF₃.

In certain embodiments, R² is tert-butyl.

In certain embodiments, R² is cyclopropyl.

In certain embodiments, R² is —OCH₃.

In certain embodiments, R² is —Si(CH₃)₃.

In certain embodiments, R² is —CONH₂.

In certain embodiments, R² is cyano.

In certain embodiments, R² is phenyl.

In certain embodiments, the compound is represented by formula II:

In certain embodiments, the compound is represented by formula IV:

In certain embodiments, the compound is represented by formula VI:

In certain embodiments, the compound is represented by formula VIII:

In certain embodiments, the compound is represented by formula X:

In certain embodiments, the compound is represented by formula XII:

In certain embodiments, the compound is represented by formula XIV:

In certain embodiments, the compound is represented by formula XVI:

In certain embodiments, the compound is represented by formula XVIII:

In certain embodiments, the compound is represented by formula XX:

In certain embodiments, the compound is represented by formula XXII:

In certain embodiments, the compound is represented by formula XXIV:

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula III:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula V:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In other aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula VII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In other aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula IX:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XI:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XIII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In some aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XV:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XVII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R³ represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XIX:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XXI:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XXIII:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula XXV:

-   -   wherein:    -   X represents CH, C(OH), C(O(C₁-C₆)alkyl), C(O)N, CH₂N, N, C(O),        or —O—; provided that:        -   if X represents CH, then —Y—R⁴ represents —H or —OH, or both            Y and R⁴ are present;        -   if X represents C(OH) or C(O(C₁-C₆)alkyl), then —Y—R⁴ is            present;        -   if X represents C(O)N, then —Y—R⁴ represents H; or —Y—R⁴            represents H, and —R³—R^(3a) represents H;        -   if X represents CH₂N, then —Y—R⁴ represents (C₁-C₆)alkyl;        -   if X represents N, then —Y—R⁴ represents H, or both Y and R⁴            are present; and        -   if X represents C(O) or —O—, then —Y—R⁴ is absent;    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl;    -   R^(1c) represents halo, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        —SO₂CH₃, formyl, acyl, or optionally substituted aryl;    -   R² represents halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₁-C₆)fluoroalkyl, —OCH₃, —Si(CH₃)₃, —CONH₂, —C(O)OH, cyano, or        phenyl;    -   R³, when present, represents —NH—, —O—, optionally substituted        aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂;    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl;

can represent

and

-   -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, X represents CH, and both Y and R⁴ are present.

In certain embodiments, —X—Y— represents —CHNHCH₂—.

In certain embodiments, —X—Y— represents —C(OH)CH₂CH₂—.

In certain embodiments, —X—Y— represents —CHOCH₂—.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ represents phenylene-R^(3a).

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments —R³—R^(3a) represents

In accordance with any one of the foregoing embodiments, in certainembodiments R^(3a) is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments R⁴ is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is ortho, meta, or para —OH.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —NH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R³ is phenyl, and R^(3a) is meta or para —CN.

In accordance with any one of the foregoing embodiments, in certainembodiments Z is absent.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents fluoro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents chloro.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or5-(C₃-C₈)cycloalkyl.

In accordance with any one of the foregoing embodiments, in certainembodiments Z represents 6-F.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents aminomethyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R^(1c) represents —SO₂CH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CH₃ or —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CF₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is tert-butyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyclopropyl.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —OCH₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —Si(CH₃)₃.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is —CONH₂.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is cyano.

In accordance with any one of the foregoing embodiments, in certainembodiments R² is phenyl.

In certain aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, represented by formula (XXVI):

-   -   wherein:    -   X represents CH, C(OH), —C(NH₂), or —C(NR^(a)R^(b));    -   —Y—R⁴, when present, represents —((C₁-C₆)alkyl)-R⁴, —CH₂C(O)—R⁴,        —CH₂NH—R⁴, —CH₂N((C₁-C₆)alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴,        —NHCH₂—R⁴, —NHC(O)—R⁴, —N((C₁-C₆)alkyl)-R⁴,        —N((C₁-C₆)alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴,        —N[(C₃-C₈)cycloalkyl(C₁-C₆)alkyl]R⁴, -heterocyclyl-R⁴, —OR⁴,        —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴, or —SR⁴,        wherein the (C₁-C₆)alkyl moiety of —((C₁-C₆)alkyl)-R⁴ is        optionally substituted;    -   Z is absent or represents halo, hydroxy, (C₁-C₆)alkyl, —CF₃,        —OCF₃, (C₁-C₆)alkoxy, aryl, aryloxy, amino, amino(C₁-C₆)alkyl,        —C(O)NH₂, cyano, —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        or (C₃-C₈)cycloalkyl; R1c represents halo, amino(C₁-C₆)alkyl,        (C₁-C₆)alkoxy, cyano, —SO₂CH₃, formyl, acyl, —NH₂, or optionally        substituted aryl;    -   R^(3a) is absent or represents one or more substituents        independently selected from the group consisting of halo,        hydroxy, (C₁-C₆)alkyl, —CF₃, —OCF₃, (C₁-C₆)alkoxy, aryl,        aryloxy, amino, amino(C₁-C₆)alkyl, —C(O)NH₂, cyano,        —NHC(O)(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, and —SO₂NH₂; and    -   R⁴ represents hydrogen, hydroxy, optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl,        heterocyclyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —CH₂OH,        —CH((C₁-C₆)alkyl)OH, —CH(NH₂)CH((C₁-C₆)alkyl)₂, optionally        substituted aryl, optionally substituted aryl(C₁-C₆)alkyl,        heteroaryl, optionally substituted heteroaryl(C₁-C₆)alkyl,        —CH₂S(C₁-C₆)alkyl, amino, or cyano; or —CH₂— fused to the        4-position of the ring bearing Z to form a 5- to 7-membered        heterocyclic ring with optional substituents;    -   or, when R³ is phenyl, can represent —NH— fused to the position        ortho to X on that phenyl.

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

In certain embodiments, the compound is selected from the groupconsisting of:

Pharmaceutical Compositions

The invention provides pharmaceutical compositions, each comprising oneor more compounds of the invention and a pharmaceutically acceptablecarrier. In certain embodiments, the pharmaceutical compositioncomprises a compound of the invention and a pharmaceutically acceptablecarrier. In certain embodiments, the pharmaceutical compositioncomprises a plurality of compounds of the invention and apharmaceutically acceptable carrier.

In certain embodiments, a pharmaceutical composition of the inventionfurther comprises at least one additional pharmaceutically active agentother than a compound of the invention. The at least one additionalpharmaceutically active agent can be an agent useful in the treatment ofa disease or condition characterized by unwanted plasma kallikreinactivity. For example, the at least one additional pharmaceuticallyactive agent can be an anticoagulation agent, an anti-platelet agent, ora thrombolytic agent.

Anticoagulation agents prevent the coagulation of blood components andthus prevent clot formation, for example in atrial fibrillation.Anticoagulants include, but are not limited to, heparin, warfarin,coumadin, dicumarol, phenprocoumon, acenocoumarol, ethyl biscoumacetate,hirudin, bivalarutin, direct thrombin inhibitors, and indandionederivatives.

Anti-platelet agents inhibit platelet aggregation and are often used toprevent thromboembolic stroke in patients who have experienced atransient ischemic attack, stroke, or atrial fibrillation. Anti-plateletagents include, but are not limited to, aspirin, thienopyridinederivatives such as ticlopodine and clopidogrel, dipyridamole, andsulfinpyrazone, as well as RGD mimetics.

Thrombolytic agents lyse clots that cause thromboembolic phenomena suchas stroke, myocardial infarction, and pulmonary thromboembolism.Thrombolytic agents include, but are not limited to, plasminogen,a2-antiplasmin, streptokinase, antistreplase, TNK, tissue plasminogenactivator (tPA), and urokinase. Tissue plasminogen activator includesnative tPA and recombinant tPA, as well as modified forms of tPA thatretain the enzymatic or fibrinolytic activities of native tPA.

Pharmaceutical compositions of the invention can be prepared bycombining one or more compounds of the invention with a pharmaceuticallyacceptable carrier and, optionally, one or more additionalpharmaceutically active agents.

Methods of Use

The present invention provides compounds that inhibit the formation ofthrombin via the intrinsic pathway and thus reduce the risk of newpathogenic thrombus formation (vessel occlusion or reocclusion) and alsoimprove fibrinolytic-induced reperfusion when given as adjunctivetherapy with a fibrinolytic regimen. Diseases and conditions that can betreated using the compounds of the present invention include, but arenot limited to, stroke, inflammation, reperfusion injury, acutemyocardial infarction, deep vein thrombosis, post fibrinolytic treatmentcondition, angina, edema, angioedema, hereditary angioedema, sepsis,arthritis, hemorrhage, blood loss during cardiopulmonary bypass,inflammatory bowel disease, diabetes mellitus, retinopathy, diabeticretinopathy, diabetic macular edema, diabetic macular degeneration,age-related macular edema, age-related macular degeneration,proliferative retinopathy, neuropathy, hypertension, brain edema,increased albumin excretion, macroalbuminuria, and nephropathy.

For example, in patients with angioedema conditions, small polypeptidePK inhibitor DX-88 (ecallantide) alleviates edema in patients withhereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher.Sci. 29:255-8; Schneider, L. et al. (2007) J Allergy Clin Immunol.120:416-22; and Levy, J. H. et al. (2006) Expert Opin. Invest. Drugs15:1077-90. A bradykinin B2 receptor antagonist, Icatibant, is alsoeffective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin.Immunol. 119:1497-1503. Because plasma kallikrein generates bradykinin,inhibition of plasma kallikrein is expected to inhibit bradykininproduction.

For example, in coagulation resulting from fibrinolytic treatment (e.g.,treatment with tissue plasminogen activator or streptokinase), higherlevels of plasma kallikrein are found in patients undergoingfibrinolysis. Hoffmeister, H. M. et al. (1998) J. Cardiovasc. Pharmacol.31:764-72. Plasmin-mediated activation of the intrinsic pathway has beenshown to occur in plasma and blood and was markedly attenuated in plasmafrom individuals deficient in any of the intrinsic pathway components.Ewald, G. A. et al. (1995) Circulation 91:28-36.

Individuals who have had an acute MI were found to have elevated levelsof activated plasma kallikrein and thrombin. Hoffmeister, H. M., et al.(1998) Circulation 98:2527-33.

DX-88 reduced brain edema, infarct volume, and neurological deficits inan animal model of ischemic stroke. Storini, C. et al. (2006)J. Pharm.Exp. Ther. 318:849-854. C₁-inhibitor reduced infarct size in a mousemodel of middle cerebral artery occlusion (MCAO). De Simoni, M. G. etal. (2004) Am. J. Pathol. 164:1857-1863; and Akita, N. et al. (2003)Neurosurgery 52:395-400). B2 receptor antagonists were found to reducethe infarct volume, brain swelling, and neutrophil accumulation and wereneuroprotective in an MCAO animal model. Zausinger, S. et al. (2003)Acta Neurochir. Suppl. 86:205-7; Lumenta, D. B. et al. (2006) Brain Res.1069:227-34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139:1539-47.

Regarding blood loss during cardiopulmonary bypass (CPB), it has beenfound that the kallikrein-kinin (i.e., contact) system is activatedduring CABG. Wachtfogel, Y. T. (1989) Blood 73:468. Activation of thecontact system during CPB results in up to a 20-fold increase in plasmabradykinin. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, D.J. et al. (2001) Am. J. Physiol. Reg. Integr. Comp. Physiol.281:1059-70.

Plasma kallikrein inhibitors P8720 and PKSI-527 have also been found toreduce joint swelling in rat models of arthritis. De La Cadena, R. A. etal. (1995) FASEB J. 9:446-52; Fujimori, Y. (1993) Agents Action 39:42-8.It has also been found that inflammation in animal models of arthritiswas accompanied by activation of the contact system. Blais, C. Jr. etal. (1997) Arthritis Rheum. 40:1327-33.

Additionally, plasma kallikrein inhibitor P8720 has been found to reduceinflammation in an acute and chronic rat model of inflammatory boweldisease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33;Stadnicki, A. et al. (1996) Dig. Dis. Sci. 41:912-20; and De La Cadena,R. A., et al. (1995) FASEB J. 9:446-52. The contact system is activatedduring acute and chronic intestinal inflammation. Sartor, R. B. et al.(1996) Gastroenterology 110:1467-81. It has been found that B2 receptorantagonist, an antibody to high molecular weight kininogen, or reductionin levels of kininogen reduced clinicopathology in animal models of IBD.Ibid.; Arai, Y. et al. (1999) Dig. Dis. Sci. 44:845-51; and Keith, J. C.et al. (2005) Arthritis Res. Therapy 7:R769-76.

H-D-Pro-Phe-Arg-chloromethylketone (CMK), an inhibitor of PK and FXIIand a physiological inhibitor (Cl-inhibitor), has been found to reducevascular permeability in multiple organs and reduce lesions inlipopolysaccharide (LPS)- or bacterial-induced sepsis in animals. Liu,D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000)J. Exp. Med.192:1415-24. Clinical improvement was observed in sepsis patientstreated with Cl-inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost.Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med.30:1722-8; and Marx, G. et al. (1999) Intensive Care Med. 25:1017-20.Fatal cases of septicemia are found to have a higher degree of contactactivation. Martinez-Brotons, F. et al. (1987) Thromb. Haemost.58:709-713; and Kalter, E. S. et al. (1985) J. Infect. Dis. 151:1019-27.

It has also been found that prePK levels are higher in diabetics,especially those with proliferative retinopathy, and correlate withfructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13:181-8; andKedzierska, K. et al. (2005) Archives Med. Res. 36:539-43. PrePK is alsofound to be highest in those with a sensorimotor neuropathy. Christie,M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3. PrePK levelsare elevated in diabetics and are associated with increased bloodpressure. PrePK levels independently correlate with the albuminexcretion rate and are elevated in diabetics with macroalbuminuria,suggesting prePK may be a marker for progressive nephropathy. Jaffa, A.A. et al. (2003) Diabetes 52:1215-21. B1 receptor antagonists have beenfound to decrease plasma leakage in rats treated with streptozotocin.Lawson, S. R. et al. (2005) Eur. J. Pharmacol. 514:69-78. B1 receptorantagonists can also prevent streptozotocin-treated mice from developinghyperglycemia and renal dysfunction. Zuccollo, A. et al. (1996) Can. J.Physiol. Pharmacol. 74:586-9.

In certain aspects, the invention provides a compound of the invention,or a pharmaceutically acceptable salt thereof, for use as a medicament.

In certain aspects, the invention provides methods of treating orpreventing a disease or condition characterized by unwanted plasmakallikrein activity. The method includes the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, therebytreating or preventing the disease or condition characterized byunwanted plasma kallikrein activity. By reducing plasma kallikreinactivity in the subject, the disease or condition characterized byunwanted plasma kallikrein activity is treated.

Alternatively, in certain aspects, the invention provides a compound ofthe invention, or a pharmaceutically acceptable salt thereof, fortreatment of a disease or condition characterized by unwanted plasmakallikrein activity.

Alternatively, in certain aspects, the invention provides the use of acompound of the invention, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use in treatment of adisease or condition characterized by unwanted plasma kallikreinactivity.

As used herein, a “disease or condition characterized by unwanted plasmakallikrein activity” refers to any disease or condition in which it isdesirable to reduce plasma kallikrein activity. For example, it may bedesirable to reduce plasma kallikrein activity in the setting of ahypercoagulable state. As another example, it may be desirable to reduceplasma kallikrein activity in the setting of tissue ischemia that isassociated with the presence or formation of thrombus.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is selected from the groupconsisting of stroke, inflammation, reperfusion injury, acute myocardialinfarction, deep vein thrombosis, post fibrinolytic treatment condition,angina, edema, angioedema, hereditary angioedema, sepsis, arthritis,hemorrhage, blood loss during cardiopulmonary bypass, inflammatory boweldisease, diabetes mellitus, retinopathy, diabetic retinopathy, diabeticmacular edema, diabetic macular degeneration, age-related macular edema,age-related macular degeneration, proliferative retinopathy, neuropathy,hypertension, brain edema, increased albumin excretion,macroalbuminuria, and nephropathy.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is angioedema.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is hereditary angioedema (HAE).

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is stroke.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is reperfusion injury.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is acute myocardial infarction.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is hemorrhage.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is blood loss during cardiopulmonarybypass.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is selected from the groupconsisting of retinopathy, diabetic retinopathy, diabetic macular edema,diabetic macular degeneration, age-related macular edema, age-relatedmacular degeneration, and proliferative retinopathy.

Formulations, Routes of Administration, and Dosing

The compounds of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient, in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally, by intravenous,intraperitoneal, intramuscular, topical, or subcutaneous routes.Additional routes of administration are also contemplated by theinvention.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2% to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing diluents and carriers: binders such as gum tragacanth, acacia,corn starch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water or physiologicallyacceptable aqueous solution, optionally mixed with a nontoxicsurfactant. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, triacetin, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, methods of preparation can includevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known in the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392; incorporatedherein by reference), Geria (U.S. Pat. No. 4,992,478; incorporatedherein by reference), Smith et al. (U.S. Pat. No. 4,559,157;incorporated herein by reference), and Wortzman (U.S. Pat. No.4,820,508; incorporated herein by reference).

Useful dosages of the compounds of the invention can be determined, atleast initially, by comparing their in vitro activity and in vivoactivity in animal models. Methods for the extrapolation of effectivedosages in mice, and other animals, to humans are known in the art; forexample, see U.S. Pat. No. 4,938,949 (incorporated herein by reference).

The amount of the compound, or an active salt thereof, required for usein treatment will vary not only with the particular compound or saltselected but also with the route of administration, the nature of thecondition being treated, and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg body weight of the recipient per day, e.g., fromabout 3 to about 90 mg/kg of body weight per day, from about 6 to about75 mg per kilogram of body weight per day, from about of 10 to about 60mg/kg of body weight per day, or from about 15 to about 50 mg/kg of bodyweight per day.

Compounds of the invention can be conveniently formulated in unit dosageform; for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500mg of active ingredient per unit dosage form. In one embodiment, theinvention provides a composition comprising a compound of the inventionformulated in such a unit dosage form. The desired dose may convenientlybe presented in a single dose or as divided doses to be administered atappropriate intervals, for example, as two, three, four or moresub-doses per day. The sub-dose itself may be further divided, e.g.,into a number of discrete loosely spaced administrations.

Compounds of the invention can also be administered in combination withother therapeutic agents, for example, other agents that are useful fortreating or preventing ischemia, blood loss, or reperfusion injury.

Other delivery systems can include time-release, delayed release, orsustained release delivery systems such as are well-known in the art.Such systems can avoid repeated administrations of the active compound,increasing convenience to the subject and the physician. Many types ofrelease delivery systems are available and known to those of ordinaryskill in the art. Use of a long-term sustained release implant may bedesirable. Long-term release, as used herein, means that the deliverysystem or is implant constructed and arranged to deliver therapeuticlevels of the active ingredient for at least 30 days, and preferably 60days.

In certain embodiments, a compound of the invention is formulated forintraocular administration, for example direct injection or insertionwithin or in association with an intraocular medical device.

The compounds of the invention may be formulated for depositing into amedical device, which may include any of a variety of conventionalgrafts, stents, including stent grafts, catheters, balloons, baskets, orother device that can be deployed or permanently implanted within a bodylumen. As a particular example, it would be desirable to have devicesand methods which can deliver compounds of the invention to the regionof a body which has been treated by interventional technique.

In exemplary embodiment, a compound of the invention may be depositedwithin a medical device, such as a stent, and delivered to the treatmentsite for treatment of a portion of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e.,drugs). Intravascular stents are generally permanently implanted incoronary or peripheral vessels. Stent designs include those of U.S. Pat.No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S.Pat. No. 4,886,062 (Wiktor). Such designs include both metal andpolymeric stents, as well as self-expanding and balloon-expandablestents. Stents may also be used to deliver a drug at the site of contactwith the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz),U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634(Narciso, Jr.), and in International Patent Application Nos. WO 91/12779(Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), forexample.

The term “deposited” means that the compound is coated, adsorbed,placed, or otherwise incorporated into the device by methods known inthe art. For example, the compound may be embedded and released fromwithin (“matrix type”) or surrounded by and released through (“reservoirtype”) polymer materials that coat or span the medical device. In thelatter example, the compound may be entrapped within the polymermaterials or coupled to the polymer materials using one or more thetechniques for generating such materials known in the art. In otherformulations, the compound may be linked to the surface of the medicaldevice without the need for a coating, for example by means ofdetachable bonds, and release with time or can be removed by activemechanical or chemical processes. In other formulations, the compoundmay be in a permanently immobilized form that presents the compound atthe implantation site.

In certain embodiments, the compound may be incorporated with polymercompositions during the formation of biocompatible coatings for medicaldevices, such as stents. The coatings produced from these components aretypically homogeneous and are useful for coating a number of devicesdesigned for implantation.

The polymer may be either a biostable or a bioabsorbable polymerdepending on the desired rate of release or the desired degree ofpolymer stability, but frequently a bioabsorbable polymer is preferredfor this embodiment since, unlike a biostable polymer, it will not bepresent long after implantation to cause any adverse, chronic localresponse. Bioabsorbable polymers that could be used include, but are notlimited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA),poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly (L-lactide)(PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA/PTMC),polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester,polyphosphoester urethane, poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters)(e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes andbiomolecules such as fibrin, fibrinogen, cellulose, starch, collagen andhyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates,cross linked or amphipathic block copolymers of hydrogels, and othersuitable bioabsorbable polymers known in the art. Also, biostablepolymers with a relatively low chronic tissue response such aspolyurethanes, silicones, and polyesters could be used, and otherpolymers could also be used if they can be dissolved and cured orpolymerized on the medical device such as polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyrancopolymer; polyhydroxy-propyl-methacrylamide-phenol;polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysinesubstituted with palmitoyl residues; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins, polyurethanes; rayon;rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

Polymers and semipermeable polymer matrices may be formed into shapedarticles, such as valves, stents, tubing, prostheses and the like.

In certain embodiments of the invention, the compound of the inventionis coupled to a polymer or semipermeable polymer matrix that is formedas a stent or stent-graft device.

Typically, polymers are applied to the surface of an implantable deviceby spin coating, dipping, or spraying. Additional methods known in theart can also be utilized for this purpose.

Methods of spraying include traditional methods as well asmicrodeposition techniques with an inkjet type of dispenser.Additionally, a polymer can be deposited on an implantable device usingphoto-patterning to place the polymer on only specific portions of thedevice. This coating of the device provides a uniform layer around thedevice which allows for improved diffusion of various analytes throughthe device coating.

In certain embodiments of the invention, the compound is formulated forrelease from the polymer coating into the environment in which themedical device is placed. Preferably, the compound is released in acontrolled manner over an extended time frame (e.g., months) using atleast one of several well-known techniques involving polymer carriers orlayers to control elution. Some of these techniques are described inU.S. Patent Application 2004/0243225A1, the entire disclosure of whichis incorporated herein in its entirety.

Moreover, as described for example in U.S. Pat. No. 6,770,729, which isincorporated herein in its entirety, the reagents and reactionconditions of the polymer compositions can be manipulated so that therelease of the compound from the polymer coating can be controlled. Forexample, the diffusion coefficient of the one or more polymer coatingscan be modulated to control the release of the compound from the polymercoating. In a variation on this theme, the diffusion coefficient of theone or more polymer coatings can be controlled to modulate the abilityof an analyte that is present in the environment in which the medicaldevice is placed (e.g. an analyte that facilitates the breakdown orhydrolysis of some portion of the polymer) to access one or morecomponents within the polymer composition (and for example, therebymodulate the release of the compound from the polymer coating). Yetanother embodiment of the invention includes a device having a pluralityof polymer coatings, each having a plurality of diffusion coefficients.In such embodiments of the invention, the release of the compound fromthe polymer coating can be modulated by the plurality of polymercoatings.

In yet another embodiment of the invention, the release of the compoundfrom the polymer coating is controlled by modulating one or more of theproperties of the polymer composition, such as the presence of one ormore endogenous or exogenous compounds, or alternatively, the pH of thepolymer composition. For example, certain polymer compositions can bedesigned to release a compound in response to a decrease in the pH ofthe polymer composition.

Kits

The invention also provides a kit, comprising a compound of theinvention, or a pharmaceutically acceptable salt thereof: at least oneother therapeutic agent, packaging material, and instructions foradministering the compound of the invention or the pharmaceuticallyacceptable salt thereof and the other therapeutic agent or agents to amammal to treat or prevent ischemia, blood loss, or reperfusion injuryin the mammal. In one embodiment, the mammal is a human.

EXAMPLES

The present invention is further illustrated by the following examples,which in no way should be construed as further limiting. The entirecontents of all the references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated by reference.

Appropriately substituted pyrazole carboxylic acid can be prepared byvarious methods as reported in the following references

-   1. Substituted pyrazolyl-based carboxamide and urea derivatives    bearing a phenyl moiety substituted with an SO2-containing group as    vanilloid receptor ligands; Frank, Robert et al; PCT Int. Appl.,    2013/068464, 16 May 2013 (incorporated by reference)-   2. Design, synthesis and biological activity of E-β-farnesene    analogues containing pyrazole-carboxamide; Sun, Yufeng et al; Youji    Huaxue, 31(9), 1425-1432; 2011-   3. Preparation of heterocyclic urea derivatives as kinase inhibitors    useful for the treatment of myeloproliferative diseases and other    proliferative diseases; Flynn, Daniel L. et al; PCT Int. Appl.,    2013/036232 (incorporated by reference).-   4. Substituted phenylureas and phenylamides as vanilloid receptor    ligands and their preparation; By Frank, Robert et al; U.S. Pat.    Appl. Publ., 2012/0258946 (incorporated by reference)-   5. Substituted cyclic carboxamide and urea derivatives as ligands of    the vanilloid receptor; Frank, Robert et al; PCT Int. Appl.,    2012/022487 (incorporated by reference)-   6. Preparation of heterocyclic urea derivatives as kinase inhibitors    useful for the treatment of hyperproliferative and other diseases;    Flynn, Daniel L. and Kaufman, Michael D; U.S. Pat. Appl. Publ.,    2012/0225057 (incorporated by reference).-   7. Preparation of pyrazolylpyrimidine derivatives for use as protein    kinase modulators; Casuscelli, Francesco et al; PCT Int. Appl.,    2012/139930 (incorporated by reference)-   8. Preparation of substituted heteroaromatic carboxamide and urea    compounds as vanilloid receptor ligands; Frank, Robert et al; U.S.    Pat. Appl. Publ., 2012/0115903 (incorporated by reference)-   9. Preparation of pyrazole derivatives as modulators of calcium    release-activated calcium channel for treatment of non-small cell    lung cancer; Muthuppalaniappan, Meyyappan et al; Indian Pat. Appl.,    2009CH02439-   10. 3-methoxy pyridine amides with good insecticidal activity and    their preparation; Li, Bin et al; Faming Zhuanli Shenqing, 102285963-   11. Preparation of amidinoaneline derivatives with inhibitory    activity to activated blood coagulation factor X; Matsumoto, Kayo et    al; PCT Int. Appl., 2011/118818 (incorporated by reference)-   12. Preparation of    1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)phenyl]urea    and related compounds as antitumor agents; Springer, Caroline et al;    PCT Int. Appl., 2011/092469 (incorporated by reference)-   13. 3-(1-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5-carboxylic    acids as peptide bond replacements; Jones, Raymond C. F. et al;    Synlett, (2), 211-214; 2011-   14. New Analogues of (E)-β-Farnesene with Insecticidal Activity and    Binding Affinity to Aphid Odorant-Binding Proteins; Sun, Yufeng et    al; Journal of Agricultural and Food Chemistry, 59(6), 2456-2461;    2011-   15. 1,2-Diamines as inhibitors of co-activator associated arginine    methyltransferase 1 (CARM1); Therrien, Eric et al; Bioorganic &    Medicinal Chemistry Letters, 19(23), 6725-6732; 2009-   16. Preparation of benzamide compounds as pesticides; Li, Bin et al;    Faming Zhuanli Shenqing Gongkai Shuomingshu, 101298451-   17. Optimization of pyrazole inhibitors of coactivator associated    arginine methyltransferase 1 (CARM1); Huynh, Tram et al; Bioorganic    & Medicinal Chemistry Letters, 19(11), 2924-2927; 2009-   18. Pyrazole derivatives as LXR and FXR modulators and their    preparation, pharmaceutical compositions and use in the treatment of    diseases; Boren, Brant Clayton et al; PCT Int. Appl., 2008/073825    (incorporated by reference)-   19. Preparation of N-(pyridylpyrimidinylaminophenyl) amides as    protein kinase inhibitors; Chianelli, Donatella et al; PCT Int.    Appl., 2008/058037 (incorporated by reference)-   20. Preparation of heterocyclic ureas as kinase inhibitors useful    for the treatment of proliferative and inflammatory diseases; Flynn,    Daniel L. et al; PCT Int. Appl., 2008/034008 (incorporated by    reference)-   21. Heterocyclic derivatives as inhibitors of protein arginine    methyltransferases and their preparation, pharmaceutical    compositions and use in the treatment of diseases, Wahhab, Amal et    al; PCT Int. Appl., 2008/104077 (incorporated by reference)-   22. Preparation of heterocyclic ureas as kinase inhibitors useful    for the treatment of proliferative and inflammatory diseases; Flynn,    Daniel L. et al; PCT Int. Appl., 2008/034008 (incorporated by    reference)-   23. Novel N-heterocyclic phosphonates and phosphinates as    glucokinase activators for treatment of Type II diabetes; Ryono,    Dennis E. et al; PCT Int. Appl., 2008/005964 (incorporated by    reference)-   24. Reductive isoxazole ring opening of the anticoagulant razaxaban    is the major metabolic clearance pathway in rats and dogs; Zhang,    Donglu et al; Drug Metabolism and Disposition, 36(2), 303-315; 2008-   25. Structure-activity relationship and pharmacokinetic profile of    5-ketopyrazole factor Xa inhibitors; Varnes, Jeffrey G. et al;    Bioorganic & Medicinal Chemistry Letters, 18(2), 749-754; 2008-   26. Preparation of (pyrazolecarbonylamino)benzamide derivatives as    insecticides and fungicides; Li, Bin et al; PCT Int. Appl.,    2008/134969 (incorporated by reference)-   27. Pyrazole inhibitors of coactivator associated arginine    methyltransferase 1 (CARM1); Purandare, Ashok V. et al; Bioorganic &    Medicinal Chemistry Letters, 18(15), 4438-4441; 2008-   28. Potent Non-Nucleoside Inhibitors of the Measles Virus    RNA-Dependent RNA Polymerase Complex; Sun, Aiming et al; Journal of    Medicinal Chemistry, 51(13), 3731-3741; 2008-   29. Design, structure-activity relationship, and pharmacokinetic    profile of pyrazole-based indoline factor Xa inhibitors; Varnes,    Jeffrey G. et al; Bioorganic & Medicinal Chemistry Letters, 17(23),    6481-6488; 2007-   30. Preparation of pyrazoles for the treatment of obesity and other    CNS disorders; Bennani, Youseff L. et al; PCT Int. Appl.,    2007/094962 (incorporated by reference)-   31. Preparation of ureidopyrazoles as kinase inhibitors,    particularly as p38 kinase inhibitors; Bastian, Jolie Anne et al;    PCT Int. Appl., 2007/053394, 10 May 2007-   32. Hydrazide compound and their preparation, formulation and    pesticidal use; Ikegami, Hiroshi et al; PCT Int. Appl., 2007/043677    (incorporated by reference)-   33. Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: A    new use of silicon bioisosteres in medicinal chemistry; Barnes,    Matthew J. et al; Bioorganic & Medicinal Chemistry Letters, 17(2),    354-357; 2007-   34. Preparation of anthranilamide derivative insecticides and    acaricides; Lahm, George Philip et al; PCT Int. Appl., 2006/055922    (incorporated by reference)-   35. Preparation of amino acid derivatives as inhibitors of protein    arginine methyl transferases; Purandare, Ashok Vinayak and Chen,    Zhong; PCT Int. Appl., 2006/069155 (incorporated by reference)-   36. Preparation of azole carboxamides as inhibitors of bacterial    type III protein secretion systems; Li, Xiaobing et al; PCT Int.    Appl., 2005/113522 (incorporated by reference)-   37. Preparation of pyrazolylbenzamides and    pyrazolopyridinylbenzamides as factor Xa inhibitors for the    treatment of thromboembolic disorders; Lam, Patrick Y. et al; U.S.    Pat. Appl. Publ., 2006/0089496 (incorporated by reference)-   38. Preparation of pyrazolylcarbonyl anthranilamides as    insecticides; Lahm, George Philip and Selby, Thomas Paul; PCT Int.    Appl., 2005/118552 (incorporated by reference)-   39. Insecticidal anthranilic diamides: A new class of potent    ryanodine receptor activators; Lahm, George P. et al; Bioorganic &    Medicinal Chemistry Letters, 15(22), 4898-4906; 2005-   40. Process for the preparation of 1,3,5-trisubstituted pyrazoles    via [3+2] cycloaddition; Shapiro, Rafael et al; U.S. Pat. Appl.    Publ., 2006/0069270 (incorporated by reference)-   41. Preparation of amides of pyrazolamines and anilines as well as    analogs as cytokine inhibitors for the treatment of inflammatory    diseases; Boman, Erik et al; PCT Int. Appl., 2005/023761    (incorporated by reference)-   42. Discovery of    1-(3′-Aminobenzisoxazol-5′-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2′-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide    Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally    Bioavailable Factor Xa Inhibitor; Quan, Mimi L. et al; Journal of    Medicinal Chemistry, 48(6), 1729-1744; 2005-   43. Preparation of N-arylheteroaryls, in particular    N-phenylpiperazinyl methanones, as inhibitors of tubulin    polymerization and their compositions for treatment of cancer;    Le-Brun, Alain et al; PCT Int. Appl., 2004/078732 (incorporated by    reference)-   44. Preparation of 1,2-azole derivatives with hypoglycemic and    hypolipidemic activity; Maekawa, Tsuyoshi et al; PCT Int. Appl.,    2003/099793 (incorporated by reference)-   45. Discovery of    1-(2-Aminomethylphenyl)-3-trifluoromethyl-N-[3-fluoro-2′-(aminosulfonyl)[1,1′-biphenyl)]-4-yl]-1H-pyrazole-5-carboxamide    (DPC602), a Potent, Selective, and Orally Bioavailable Factor Xa    Inhibitor; Pruitt, James R. et al; Journal of Medicinal Chemistry,    46(25), 5298-5315; 2003-   46. 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa    inhibitors. Part 3: Design, synthesis and SAR of orally bioavailable    benzamidine-P4 inhibitors; Jia, Zhaozhong J. et al; Bioorganic &    Medicinal Chemistry Letters, 14(5), 1229-1234; 2004-   47. Preparation of novel    N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides    as factor Xa inhibitors; Quan, Mimi L; PCT Int. Appl., 2003/047517    (incorporated by reference)-   48. Preparation of imidazolylphenylpyrazolopyridinones as factor Xa    inhibitors; Quan, Mimi L. and Wexler, Ruth R; PCT Int. Appl.,    2003/047520 (incorporated by reference)-   49. Preparation of novel substituted 1H-dihydropyrazoles; Annis,    Gary David et al; PCT Int. Appl., 2003/016282 (incorporated by    reference)-   50. Pesticidal compositions for coating plant propagation material    containing anthranilamides; Berger, Richard Alan and Flexner, John    Lindsey; PCT Int. Appl., 2003/024222 (incorporated by reference)-   51. Method for controlling particular insect pests by applying    anthranilamide compounds; Lahm, George Philip et al; PCT Int. Appl.,    2003/015518 (incorporated by reference)-   52. Design, synthesis and biological activity of novel non-amidine    factor Xa inhibitors. Part 1: P1 structure-activity relationships of    the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides; Jia,    Zhaozhong J. et al; Bioorganic & Medicinal Chemistry Letters,    12(12), 1651-1655; 2002-   53. Efficient process for the preparation of a factor Xa inhibitor;    Sunkara, Hari Babu and Yang, Yali; PCT Int. Appl., 2002/024690    (incorporated by reference), 28 Mar. 2002-   54. Preparation of pyrazolecarboxamides as inhibitors of factor Xa;    Zhu, Bing-yan et al; U.S. Pat. Appl. Publ., 2002/0091116    (incorporated by reference)-   55. Preparation of dihydrobenzo[b][1,4]diazepin-2-ones as mGluR2    antagonists for treatment of neurological disorders; Adam, Geo et    al; PCT Int. Appl., 2002/083652 (incorporated by reference)-   56. Preparation of azole inhibitors of cytokine production; Bamaung,    Nwe Y. et al; U.S. Pat. Appl. Publ., 2001/0044445 (incorporated by    reference)-   57. Parallel Synthesis of Potent, Pyrazole-Based Inhibitors of    Helicobacter pylori Dihydroorotate Dehydrogenase; Haque, Tasir S. et    al; Journal of Medicinal Chemistry, 45(21), 4669-4678; 2002-   58. Preparation of 1,3,5-trisubstituted pyrazoles for pharmaceutical    use as factor Xa inhibitors; Zhou, Jiacheng et al; PCT Int. Appl.,    2001/029006 (incorporated by reference)-   59. Discovery of    1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide    (DPC423), a Highly Potent, Selective, and Orally Bioavailable    Inhibitor of Blood Coagulation Factor Xa; Pinto, Donald J. P. et al;    Journal of Medicinal Chemistry, 44(4), 566-578; 2001-   60. Preparation of novel guanidine mimics as factor Xa inhibitors;    Lam, Patrick Y. et al; PCT Int. Appl., 98/57951 (incorporated by    reference)-   61. Some reactions of β-aroylacrylic acid epoxide; By El-Sawy, A. A.    et al; Journal of the Serbian Chemical Society, 56(10), 587-94; 1991-   62. The effect of 1,3-diphenylpyrazolecarboxylic acid derivatives on    the hepatic cytochrome P-450 system; Khlopushina, T. G. et al;    Khimiko-Farmatsevticheskii Zhurnal, 25(11), 10-13; 1991-   63. Preparation and testing of phenylpyrazolecarboxylates as plant    growth regulators and protectants; Sohn, Erich et al; Ger. Offen.,    3633840-   64. Action of nitrogen nucleophiles on oxiranes of β-aroylacrylic    acids; Omran, S. A. et al; Egyptian Journal of Chemistry, 28(5),    399-410; 1986-   65. The sequential lithiation of 1-phenylpyrazoles; Micetich,    Ronald G. et al; Heterocycles, 23(4), 943-51; 1985

Preparation of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid (9i)Step-1: Preparation of3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9f)

To a suspension of 3-bromoaniline (9a) (30.8 mL, 283 mmol) in 12 Nhydrogen chloride (85 mL, 1017 mmol) was added a solution of sodiumnitrite (23.39 g, 339 mmol) in water (160 mL) at 0° C. slowly. Afterstirring for 1 h, to the mixture was added tin(II) chloride dihydrate(127 g, 565 mmol) pre-dissolved in 12 N hydrogen chloride (85 mL, 1017mmol) at such a rate that the temperature was not allowed to cross 5 OC.After stirring for 2 h, a solution of 1,1,1-trifluoropentane-2,4-dione(9c) (39.4 mL, 325 mmol) in ethanol (650 mL) was added to the crudereaction mixture containing (3-bromophenyl)hydrazine (9b) and themixture was heated at 60° C. overnight. After cooling to roomtemperature, the solvent was removed and the aqueous solution wasbasified with solid NaHCO₃ and diluted with water (300 mL), partitionedwith ethyl acetate (3×500 mL). Organic phase was dried over MgSO₄,concentrated to afford mixtures of1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (9d) and1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole (9e) (81.6 g,94.6% yield) as crude. The reaction mixture was taken as such to nextstep.

A mixture of 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole(9d) and 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole (9e)(6.1 g, 20 mmol) in DMF (15 mL) was added copper cyanide (2.24 g, 25mmol) and heated to refluxed overnight. TLC (ethyl acetate/hexanes, 20%)showed reaction complete. The reaction mixture was diluted with ethylacetate (200 mL), and filtered. The filtrate was washed with water (200mL) and brine (100 mL) and dried. The crude mixture was purified with a80 g silica gel flash column with (ethyl acetate/hexanes, 0-50%) aseluent to furnish

-   -   1. 3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile        (9g) (0.5 g, 20% yield, higher running spot) as yellow oil. ¹H        NMR (300 MHz, DMSO-d₆) δ 8.10-8.02 (m, 2H), 7.92-7.76 (m, 2H),        7.03 (s, 1H), 2.32 (s, 3H); IR (KBr) 3143, 3084, 2934, 2236,        1565, 1498, 1463, 1366, 1302, 1238, 1194, 1147, 1008, 800, 685,        507 cm-1; Analysis, calculated for C₁₂H₈F₃N₃: C, 57.37; H, 3.21;        N, 16.73; Found: C, 57.58; H, 3.35; N, 16.83.    -   2. 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile        (9f) (1.2 g, 4.78 mmol, 48% yield, lower running spot) as a        white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.17 (t, J=1.7 Hz, 1H),        8.06-7.92 (m, 2H), 7.79 (t, J=8.0 Hz, 1H), 6.83 (s, 1H), 2.40        (d, J=0.5 Hz, 3H). IR (KBr) 3153, 3082, 2928, 2231, 1588, 1488,        1434, 1379, 1252, 1189, 1126, 969, 890, 812, 701. cm-1;        Analysis, calculated for C₁₂H₈F₃N₃: C, 57.37; H, 3.21; N, 16.73;        Found: C, 57.58; H, 3.35; N, 16.83.

Step-2: Preparation of3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(9h)

To a solution of3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9f) (2.66g, 10.59 mmol) in carbon tetrachloride (80 mL) was added1-bromopyrrolidine-2,5-dione (NBS, 1.98 g, 11.12 mmol) andbenzoylperoxide (0.077 g, 0.318 mmol). The reaction mixture was refluxedfor 4 h, cooled, filtered, and concentrated to give the crude bromide.The crude bromide was dissolved in a mixture of dioxane (40 mL) andwater (40 mL), and calcium carbonate (1.91 g, 19.06 mmol) was added. Thesolution was heated at 60° C. overnight under constant stirring. Thereaction mixture was cooled to room temperature, filtered and thefilter-cake was washed with ethyl acetate, the filtrate was concentratedto remove volatile solvent, the aqueous solution was extracted withethyl acetate (2×150 mL). The organic layers were combined, dried overMgSO₄, concentrated to give crude3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(9h). The crude was purified by purified by flash column chromatography[silica gel 40 g, eluting with 0-50% ethyl acetate/hexanes) to furnish3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(9h) (520 mg, 1.946 mmol, 18.38% yield) as a white solid. ¹H NMR (300MHz, CDCl₃) δ 8.06 (t, J=1.7 Hz, 1H), 7.99 (ddd, J=8.1, 2.1, 1.2 Hz,1H), 7.75 (dt, J=7.7, 1.3 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 6.76 (s, 1H),4.72 (t, J=9.8 Hz, 2H), 2.13 (t, J=5.5 Hz 1H); IR(KBr) 3370, 3076, 2946,2235, 1484, 1463, 1256, 1192, 1127, 1019, 805, 691, 503 cm⁻¹; Analysiscalculated for C₁₂H₈F₃N₃₀: C, 53.94; H, 3.02; N, 15.73; Found: C, 53.96;H, 3.07; N, 15.48.

Step-3: Preparation of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)

To 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(9h) (20.21 g, 76 mmol) in acetonitrile (100 mL) was added sodiumperiodate (32.4 g, 151 mmol), water (100 mL), and ruthenium(III)chloride hydrate (0.341 g, 1.513 mmol). The reaction mixture was stirredat room temperature for 16 h. The reaction mixture was filtered andconcentrated to remove acetonitrile. The aqueous layer was basified with1 N NaOH followed by ether washings (2×100 mL) to remove organicimpurities. The basic aqueous layer was acidified with 1 N HCl,extracted with ether (2×150 mL), ether layer was concentrated to approx.75 mL then hexanes were added until turbidity was seen then stirred atroom temperature overnight. The solid obtained was collected byfiltration dried in vacuum to afford1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(7.48 g, 35% yield) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ13.84 (bs, 1H), 8.22 (t, J=1.7 Hz, 1H), 8.06-8.00 (m, 1H), 7.96 (ddd,J=8.2, 2.1, 1.1 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.57 (d, J=0.4 Hz, 1H);¹⁹F NMR (282 MHz, DMSO) δ −60.96 (s); Analysis calculated for:C₁₂H₆F₃N₃₀₂: C, 51.26; H, 2.15; N, 14.94; Found: C, 51.19; H, 2.14; N,14.58.

Preparation of1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (10d) Step-1: Preparation of3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (10c)

To a 1.0 L three-neck flask containing a suspension of3-aminobenzonitrile (5 g, 42.3 mmol) in 12 N HCl (12.70 mL, 152 mmol)was added slowly at 0° C. an aqueous solution of sodium nitrite (3.50 g,50.8 mmol) in water (15 mL). The solid suspension was stirred for 1 hand to this was added a pre-dissolved solution of tin(II) chloridedihydrate (19.10 g, 85 mmol) in 12 N HCl (12.70 mL, 152 mmol) at such arate that the internal temperature was not allowed to exceed 5° C. Afterstirring for 2 h at 0-5° C. a solution of4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (10.47 g, 50.8mmol) in ethanol (61 mL) was added to the mixture and the mixture washeated at 60° C. overnight. The reaction mixture was cooled to roomtemperature, concentrated in vacuum to remove ethanol, basified withaqueous NaHCO₃ (25 g in 250 mL), diluted with water (250 mL) andextracted with ethyl acetate (3×50 mL). Organic layers were combineddried over MgSO₄, filtered, and concentrated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography [silica gel120 g, eluting with ethyl acetate in hexanes, 0-100%] to furnish afford3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (10c)(8.91 g, 69.4% yield) as a white solid.

Step-2: Preparation of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)

To a solution of3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (10c)(4.15 g, 13.69 mmol) in acetone (75 mL) was added an aqueous solution ofpotassium permanganate (15.14 g, 96 mmol) in water (75 mL). This mixturewas heated at 60° C. for 2 h and cooled to room temperature. Thereaction mixture was quenched with 2-propanol (75 mL) and stirred atroom temperature overnight. The reaction mixture was filtered throughCelite and solid cake was washed with acetone/water mixture (2×50 mL),methanol (2×50 mL). The filtrate was evaporated under reduced pressureto remove organic solvents. The aqueous was basified with 1 N NaOH, andwashed with ether (2×100 mL). The aqueous layer was poured on to crushedice, acidified very carefully with aqueous 2 N HCl under constantstirring. The solid obtained was collected by filtration, washed withhexanes (2×50 mL), dried over P205 to furnish1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic (9i)(2.68 g, 69.6% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ14.01 (s, 1H), 8.22 (t, J=1.8 Hz, 1H), 8.03 (dt, J=7.7, 1.3 Hz, 1H),7.96 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.58 (d,J=0.7 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.95.

Step-3: Preparation of1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d)

To a stirred solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic (9i) (100g, 356 mmol) in anhydrous methanol (1000 mL), cooled to 0° C. was added,nickel(II) chloride hexahydrate (8.45 g, 35.6 mmol), followed by sodiumborohydride (53.8 g, 1423 mmol) in small portions over a period of 70mins maintaining internal temperature between 0-5° C. The reactionmixture was stirred for additional 15 mins. A cold solution of NaOH(28.4 g, 711 mmol) in water (250 mL), di-tert-butyl dicarbonate (124 g,569 mmol) and THF (500 mL) was added at 0° C. After 2 h additionaldi-tert-butyl dicarbonate (15.52 g, 71.1 mmol) in THF (100 mL) was addedand continued stirring for 10 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (38 mL, 356 mmol) stirred for 30minutes and concentrated in vacuum. The solid obtained was dissolved inwater (3000 mL) and insoluble material was removed by filtration over apad of celite. The filtrate was acidified by dropwise addition of 1 NPotassium bisulfate (2134 mL, 2134 mmol, pH ˜2) over a period of 1 hmaintaining the internal temperature between 0-5° C. The solid separatedwas collected by filtration washed with water (500 mL) and dissolved indichloromethane (4000 mL). The dichloromethane layer was washed withwater (1000 mL), brine (1000 mL), dried (MgSO₄), filtered andconcentrated in vacuum. The residue obtained was purified by flashchromatography {2 Kg silicagel eluting with CMA 80 in chloroform (0%, 5%and 10% [4000 mL each], 20%, 30% and 40% [2000 mL each] 50% 10,000 mLand 60% 4000 mL)} to afford1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (97 g, 252 mmol, 70.8% yield) as light green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 7.49 (t, J=6.3 Hz, 1H), 7.36 (m, 5H), 4.20 (d,J=6.0 Hz, 2H), 1.38 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75.

Preparation of1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid(11c) Step-1: Preparation of5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b)

To a suspension of 4-methoxyaniline (3.08 g, 25 mmol) in hydrogenchloride (7.50 mL, 90 mmol) was added dropwise a solution of sodiumnitrite (2.070 g, 30.0 mmol) in water (13 mL) at 0° C. After stirringfor 1 h, to this mixture was added tin(II) chloride dihydrate (11.28 g,50.0 mmol) pre-dissolved in hydrogen chloride (7.50 mL, 90 mmol) at sucha rate that the temperature was not allowed to exceed 5° C. Afterstirring for 2 h, a solution of4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (5.67 g, 27.5 mmol)in ethanol (52 mL) was added to the mixture and the mixture was heatedat 60° C. overnight. After cooling to room temperature, the solidobtained was collected by filtration washed with water and dried invacuo to furnish5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b)(5.93 g, 19.22 mmol, 77% yield) as a grey solid; MP: 81.1° C.; ¹HNMR(300 MHz, DMSO-d₆) δ 7.78 (dd, J=1.8, 0.7 Hz, 1H), 7.46-7.42 (m, 2H),7.22 (s, 1H), 7.12-7.08 (m, 2H), 6.54 (dd, J=3.5, 1.8 Hz, 1H), 6.12 (dd,J=3.5, 0.7 Hz, 1H), 3.85 (s, 3H); ¹⁹F NMR (300 MHz, DMSO-d₆) δ −60.39;MS (ES+) 309.0.

Step-2: Preparation of1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid(11c)

To a solution of5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b)(5 g, 16.22 mmol) dissolved in acetone (180 mL) was added a solution ofKMnO₄ (17.94 g, 114 mmol) in water (200 mL). The reaction mixture washeated at 60° C. for 3 h and cooled to room temperature. The reactionmixture was quenched with IPA (180 mL) and stirred at room temperatureovernight. The reaction mixture was filtered through a pad of Celitewashed with acetone and water. The filtrate was concentrated to removeorganic solvent. The aqueous solution was acidified with acetic acid topH 4-5, and extracted with ether. The organic phase was dried overMgSO₄, filtered and concentrated in vacuum to give1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(11c) (3.965 g, 13.85 mmol, 85% yield) as light yellow solid, ananalytical sample was obtained by column purification of a small portionof the crude. ¹H NMR (300 MHz, DMSO-d₆) δ 13.34 (s, 1H), 7.50-7.38 (m,3H), 7.10-6.99 (m, 2H), 3.83 (s, 3H); MS (ES+) 287.0 (M+1).

Preparation of1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid(12c) Step-1: Preparation of1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b)

To a suspension of 4-chloroaniline (12a) (3.19 g, 25 mmol) in hydrogenchloride (7.50 mL, 90 mmol) was added dropwise a solution of sodiumnitrite (2.070 g, 30.0 mmol) in water (13 mL) at 0° C. After stirringfor 1 h, to this mixture was added tin(II) chloride dihydrate (11.28 g,50.0 mmol) pre-dissolved in hydrogen chloride (7.50 mL, 90 mmol) at sucha rate that the temperature was not allowed to exceed 5° C. Afterstirring for 2 h, a solution of4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (5.67 g, 27.5 mmol)in ethanol (52 mL) was added to the mixture and the mixture was heatedat 60° C. overnight. After cooling to room temperature, the reactionmixture was neutralized to pH=4 using 10 N NaOH (18 mL) and 1 N NaOH.The reaction mixture was concentrated in vacuum to remove ethanol. Thesolid obtained was collected by filtration washed with water and driedunder vacuum. The residue was taken in 100 mL Saturated aqueous NaHCO₃and extracted with ethyl acetate (300 mL). The organic layer was driedand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (Silica gel 40 g, eluting with 0-50% ethyl acetatein hexane) to furnish1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b)(6.238 g, 19.95 mmol, 80% yield) as a white solid; MP 62° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 7.79 (dd, J=1.9, 0.7 Hz, 1H), 7.68-7.61 (m, 2H),7.59-7.52 (m, 2H), 7.31 (d, J=0.6 Hz, 1H), 6.58 (dd, J=3.5, 1.8 Hz, 1H),6.40 (dd, J=3.5, 0.7 Hz, 1H); ¹⁹F NMR (300 MHz, DMSO-d₆) D D 060.90; MS(ES+) 314.9 (M+1).

Step-2: Preparation of1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid(12c)

To a solution of1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b)(6.23 g, 19.92 mmol) dissolved in acetone (200 mL) was added a solutionof KMnO₄ (22.04 g, 139 mmol) in water (220 mL). The reaction mixture wasstirred at 60° C. for 3 h and cooled to room temperature. The reactionmixture was quenched with IPA (200 mL) and stirred at room temperatureovernight. The reaction mixture was filtered through a pad of Celite,washed with acetone and water. The filtrate was concentrated to removeorganic solvent. The aqueous solution was acidified with acetic acid topH 4-5, and extracted with ether. The organic layer was dried, filteredand concentrated in vacuum to give 6.7g of crude material, which waspurified by flash column chromatography (silica gel 80 g, eluting withmethanol in chloroform) to furnish1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(12c) (2.5 g, 8.60 mmol, 43.2% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 14.06 (bs, 1H), 7.61-7.56 (m, 3H), 7.53-7.48 (m, 1H), 7.42(d, J=3.2 Hz, 1H); MS (ES+) 328.8 (M+K).

Preparation of1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (13d) Step-1: Preparation of 5-chloro-2-hydrazinylpyridine (13b)

A solution of 2,5-dichloropyridine (13a) (7.4 g, 50.0 mmol) andhydrazine hydrate (101 mL, 3250 mmol) in Pyridine (100 mL) was heated atreflux for 6 h and concentrated in vacuum to dryness. The residueobtained was dissolved in DCM (500 mL), washed with 1 N aqueous NaOH(500 mL), water (3×500 mL). The organic layer was dried over MgSO₄filtered and concentrated in vacuum to dryness to furnish5-chloro-2-hydrazinylpyridine (13b) (2.95 g, 20.55 mmol, 41% yield) aslight yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (d, J=2.5 Hz, 1H),7.67 (s, 1H), 7.50 (dd, J=9.0, 2.6 Hz, 1H), 6.73 (dd, J=9.0, 0.6 Hz,1H), 4.17 (s, 2H); MS (ES+) 144.2 (M+1).

Step-2: Preparation of5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine(13c)

To a solution of 5-Chloro-2-hydrazinylpyridine (13b) (717.87 mg, 5.00mmol) in EtOH (12 mL) was added4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (1134 mg, 5.50mmol), Water (3 mL), and hydrogen chloride (conc. HCl, 1.667 mL, 20.00mmol). The resulting mixture was stirred at reflux overnight andconcentrated in vacuum to remove organic solvent. The aqueous wasbasified with 1 N NaOH, and then partitioned twice with ethyl acetate.The organic layers were combined, dried filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-50% ethyl acetate inhexane) to furnish5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine(13c)

(795 mg, 2.53 mmol, 50.7% yield) as light yellow solid, ¹H NMR showed amixture of 2 compound, with a ratio of 2:1. MS (ES+) 314.0 (M+1), 335.9(M+Na).

Step-3: Preparation of1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (13d)

To a solution of5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine(13c) (750 mg, 2.39 mmol) in acetone (25 mL) and water (27.5 mL) wasadded KMnO₄ (2645 mg, 16.74 mmol). The reaction mixture was heated at60° C. for 3 h. The reaction mixture was cooled to room temperature,quenched with isopropanol (25 mL) and stirred at room temperatureovernight. The reaction mixture was filtered through a pad of Celite andthe filter-cake was washed with 50 mL of acetone-water (1:1). Thefiltrate was concentrated to remove organic solvents, and the resultingaqueous solution was acidified with 1 N HCl to pH 2-3. The solutionbecame cloudy; the solid obtained was collected by filtration washedwith some additional water, hexanes, and dried under vacuum to furnish5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine(13c) (345 mg, 1.183 mmol, 49.5% yield) as off-white solid. ¹H NMR (300MHz, DMSO-d₆) δ 13.67 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.7,2.6 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.54 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −56; MS (ES+) 292.0 (M+1), 313.9 (M+Na), 329.9 (M+K).

Preparation of1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (14d) Step-1: Preparation of1-(6-Bromonaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14b)

To a suspension of 6-bromonaphthalen-2-amine (14a) (2.6 g, 11.71 mmol)in hydrogen chloride (7.02 mL, 84 mmol) was added a solution of sodiumnitrite (0.969 g, 14.05 mmol) in water (12 mL) at 0° C. slowly. Afterstirring for 1 h, to this mixture was added tin(II) chloride dihydrate(5.28 g, 23.41 mmol) pre-dissolved in hydrogen chloride (7.02 mL, 84mmol) at such a rate that the temperature was not allowed to exceed 5°C. After stirring for 2 h, a solution of4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (2.65 g, 12.88mmol) in ethanol (24 mL) was added to the mixture and heated at 60° C.overnight. After cooling to room temperature, the reaction mixture wasbasified to pH=8 using 10 N aqueous NaOH (15 mL) and saturated NaHCO₃.The reaction mixture was diluted with ethyl acetate and filtered througha pad of celite. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (50 mL). The organic layers werecombined dried, filtered and concentrated in vacuum to furnish cruderesidue which was purified by flash column chromatography (silica gel 12g, eluting 0-100% ethyl acetate in hexane) to afford1-(6-Bromonaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14b) (1.3 g, 3.19 mmol, 27.3% yield) as a semisolid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.39 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.10 (d,J=8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.78 (dd, J=8.8, 2.0 Hz, 1H),7.75 (dd, J=1.8, 0.8 Hz, 1H), 7.64 (dd, J=8.8, 2.2 Hz, 1H), 7.35 (s,1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 6.32 (dd, J=3.5, 0.7 Hz, 1H); ¹⁹F NMR(300 MHz, DMSO-d₆) δ −60.85; MS (ES+) 406.9, 408.8 (M+1).

Step-2: Preparation of1-(6-Chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c)

To a solution of1-(6-Bromonaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14b) (1.73 g, 4.25 mmol) in DMF (25 mL) was added copper(I)iodide(0.809 g, 4.25 mmol), copper(I) chloride (4.21 g, 42.5 mmol) and heatedat reflux overnight. The mixture was cooled to room temperature dilutedwith water (35 mL) and stirred for 1 h. The precipitated solid wascollected by filtration, washed several times with water and dried undervacuum to afford1-(6-Chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c) (22 gms) contaminated with copper salts. The solid was suspendedin ethyl acetate (100 mL) and filtered. The filtrate was concentrated invacuum to dryness to yield1-(6-Chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c) (1.2 g, 3.31 mmol, 78% yield) as a light yellow solid afterpurification by column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexane); ¹HNMR (300 MHz, DMSO-d₆) δ 8.23 (t,J=1.6 Hz, 2H), 8.10 (dd, J=9.0, 1.5 Hz, 2H), 7.75 (dd, J=1.9, 0.7 Hz,1H), 7.66 (ddd, J=8.7, 6.6, 2.2 Hz, 2H), 7.35 (s, 1H), 6.53 (dd, J=3.5,1.8 Hz, 1H), 6.32 (dd, J=3.5, 0.8 Hz, 1H); Analysis calculated forC₁₈H₁₀ClF₃N₂O: C, 59.60; H, 2.78; N, 7.72; Cl, 9.77; Found: C, 59.34; H,2.60; N, 7.70; Cl, 9.96.

Step-3: Preparation of1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (14d)

To a solution of1-(6-chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c) (4.42 g, 12.19 mmol) in acetone (120 mL) was added a solution ofKMnO₄ (13.48 g, 85 mmol) in water (120 mL). The reaction mixture wasstirred at 60° C. for 3 h, cooled to room temperature, quenched withisopropanol (120 mL) and stirred at room temperature overnight. Thereaction mixture was filtered through a pad of Celite, washed withacetone and water. The filtrate was concentrated in vacuum to removeorganic solvents. The aqueous solution was washed with ether thenacidified with 1 N aqueous HCl to pH 4. The aqueous layer was extractedpartitioned with ethyl acetate dried, filtered and concentrated invacuum to furnish1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (14d) (0.86 g, 2.52 mmol, 21% yield) as light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 13.95 (s, 1H), 8.22 (dd, J=8.0, 2.1 Hz, 2H), 8.08(dd, J=13.5, 8.9 Hz, 2H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.66 (dd, J=8.8,2.1 Hz, 1H), 7.58 (s, 1H); MS (ES+) 340.9 (M+1); 338.7 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15g) Step-1: Preparation of (4-Amino-3-fluorophenyl)methanol (15b)

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF(20 mL) was added dropwise at 0° C. a solution of4-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in THF (20 mL). Thereaction mixture was stirred at room temperature overnight. The mixturewas then cooled down to 0° C., quenched with ethyl acetate (30 mL) andwater (10 mL). The slurry obtained was filtered through Celite andwashed with ethyl acetate (50 mL). The aqueous layer was separated andorganic layer was dried, filtered and concentrated in vacuum to drynessto give crude product. The crude was purified by flash columnchromatography (silica gel 80 g, eluting with 0-100% ethyl acetate inhexane) to furnish (4-Amino-3-fluorophenyl)methanol (15b) (2.2 g, 48.4%yield) as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.91 (dd, J=12.5, 1.8Hz, 1H), 6.81 (dd, J=8.1, 1.8 Hz, 1H), 6.70 (dd, J=9.3, 8.0 Hz, 1H),5.03-4.93 (m, 3H), 4.31 (d, J=5.5 Hz, 2H); MS (ES+) 142.0 (M+1); (ES−)140.0 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15c)

In a 100 mL single-necked flask was charged with1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.99 g, 7.09 mmol), (4-amino-3-fluorophenyl)methanol (15b) (1 g, 7.09mmol), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop)(3.3 g, 7.09 mmol) was treated with N,N-dimethylformamide (42.8 mL, 553mmol) and N-ethyl-N-isopropylpropan-2-amine (6.17 mL, 35.4 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder nitrogen atmosphere. The reaction was diluted with water (150 mL),and extracted with ethyl acetate (2×150 mL), washed with brine (75 mL),the combined organic layer was dried over anhydrous MgSO₄, filtered, andevaporated to dryness. The residue was purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15c) (1.151 g, 2.85 mmol, 40.2% yield) as a pale yellow solid; MS(ES⁺): MS (ES+) 405.2 (M+1), MS (ES−) 403.2 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15d)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15c) (1.106 g, 2.74 mmol) in dichloromethane (20 mL) was added sodiumbicarbonate (1.149 g, 13.68 mmol), Dess-Martin Periodinane (1.74 g, 4.10mmol) and stirred at room temperature for 5 h. Additional Dess-MartinPeriodinane (1.74 g, 4.10 mmol), was added to the reaction and stirredfor 30 min. Excess solvent was pumped-off under reduced pressure. Thereaction mixture was diluted with water (50 mL), and extracted withethyl acetate (2×75 mL). The combined organic layer was dried overanhydrous MgSO₄, filtered and evaporated to dryness. The residueobtained was purified by flash column chromatography [(silica gel 25 g,eluting with ethyl acetate/hexanes from 0 to 100%)] to furnish1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15d) (0.418 g, 38.0% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H, D₂O exchangeable), 9.95 (d,J=1.7 Hz, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.04-7.98 (m, 1H), 7.97-7.90 (m,2H), 7.85-7.78 (m, 3H), 7.74 (t, J=8.0 Hz, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.97, −120.36; MS (ES⁺): MS (ES+) 425.08 (M+Na), MS (ES−)401.1 (M−1).

Step-4: Preparation of:1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15e)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15d) (0.4 g, 0.994 mmol) in THF (10 mL) cooled to 0° C. was addeddropwise phenyl magnesium bromide (2.018 mL, 2.018 mmol). The reactionmixture was stirred at room temperature for 16 h and with quenched withsaturated aqueous NH₄Cl (60 mL). The product was extracted twice withethyl acetate (100 mL, 75 mL). The combined organic extracts were driedover anhydrous MgSO₄, filtered, and concentrated in vacuum. The residueobtained was purified by flash column chromatography [(silica gel 25 g,eluting with ethyl acetate in hexanes from 0 to 100%)] to afford1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15e) (0.377 g, 0.785 mmol, 79% yield) as a waxy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.12 (t, J=1.8 Hz, 1H), 7.99(dt, J=7.7, 1.4 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.67(m, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.3Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.22 (m, 1H), 7.20 (dt, J=8.6, 2.4 Hz,2H), 6.06 (d, J=4.0 Hz, 1H, D₂O exchangeable), 5.71 (d, J=4.0 Hz, 1H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98, −121.26; IR (KBr, cm⁻¹): 2236 cm⁻¹(C—N stretching); MS (ES⁺): MS (ES+) 503.15 (M+Na), MS (ES−) 479.24(M−1).

Step-5: Preparation of1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15f)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15e) (0.453 g, 0.943 mmol) in cyclopropylmethanol (6.77 mL, 94 mmol)was added Ytterbium(III) trifluoromethanesulfonate (1.170 g, 1.886 mmol)and heated at 80° C. for 16 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was diluted with chloroform(2×50 mL), filtered through small Celite pad. The filtrate wasconcentrated in vacuum to dryness and the residue obtained was purifiedby flash column chromatography [silica gel 25 g, eluting with ethylacetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15f) (0.076 g, 15% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H, D₂O exchangeable), 8.11 (t, J=1.8 Hz, 1H), 7.99 (dt,J=7.7, 1.3 Hz, 1H), 7.89 (dd, J=8.5, 1.8 Hz, 1H), 7.77-7.68 (m, 2H),7.51 (t, J=8.0 Hz, 1H), 7.40-7.32 (m, 4H), 7.32-7.24 (m, 2H), 7.19 (dd,J=8.3, 1.9 Hz, 1H), 5.49 (s, 1H), 3.24 (d, J=6.8 Hz, 2H), 1.11-1.02 (m,1H), 0.53-0.41 (m, 2H), 0.20-0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.98, −120.92; MS (ES⁺): MS (ES+) 557.1 (M+1), MS (ES−) 533.1 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15g)

To a stirred solution of1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15f) (0.071 g, 0.133 mmol) in anhydrous methanol (10 mL) at 0° C., wasadded nickel(II) chloride hexahydrate (0.047 g, 0.199 mmol) and sodiumborohydride (0.060 g, 1.594 mmol) in small portions over a period of 5min. The reaction mixture was stirred for 10 min, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.143 mL, 1.328 mmol) and stirredfor additional 30 min. Excess methanol was pumped-off under reducedpressure. The reaction mixture was treated with sat. NH₄Cl (50 mL), andproduct was extracted with chloroform (2×50 mL). The combined organiclayers were dried over MgSO₄, filtered, evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 12 g,eluting with methanol in chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15g) (48 mg, 67% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.58 (s, 1H), 7.55 (d, J=4.6 Hz, 2H), 7.51 (d, J=3.8 Hz, 1H), 7.45-7.40(m, 2H), 7.39-7.28 (m, 6H), 7.26 (dd, J=6.0, 2.1 Hz, 1H), 7.19 (dd,J=8.3, 1.8 Hz, 1H), 5.49 (s, 1H), 3.76 (s, 2H), 3.24 (d, J=6.7 Hz, 2H),1.13-1.00 (m, 1H), 0.53-0.41 (m, 2H), 0.21-0.11 (m, 2H); ¹H NMR (300MHz, DMSO-d₆ D₂O) δ 7.55 (s, 2H), 7.53-7.48 (m, 1H), 7.45-7.40 (m, 2H),7.39-7.28 (m, 6H), 7.27-7.23 (m, 1H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 5.49(s, 1H), 3.75 (s, 2H), 3.24 (d, J=6.7 Hz, 2H), 1.06 (m, 1H), 0.56-0.41(m, 2H), 0.20-0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.74,−121.19; MS (ES⁺): MS (ES+) 539.2 (M+1), MS (ES−) 537.2 (M−1).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(16b) Step-1: Preparation of tert-Butyl3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(16a)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(15e), (0.284 g, 0.59 mmol) in anhydrous methanol (5 mL), cooled to 0°C., was added di-tert-butyl dicarbonate (0.258 g, 1.182 mmol) andnickel(II) chloride (0.035 g, 0.148 mmol), Sodium borohydride (0.134 g,3.55 mmol) was added to the reaction mixture in small portions over a 15min period. The reaction mixture was stirred for 15 min at 0° C. TLC(50% EtOAc in hexanes) shows all starting material was consumed. Thereaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine(0.128 mL, 1.182 mmol) stirred for 30 mins and concentrated in vacuum todryness. The residue obtained was dissolved in dichloromethane (20 mL)and water (20 mL). The organic layer was separated, dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 12 g, eluting with 0-100% ethylacetate in hexane) to furnish tert-Butyl3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(16a) (0.185 g, 0.316 mmol, 53.5% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.57 (s, 1H), 7.50 (q, J=7.7Hz, 2H), 7.44-7.37 (m, 3H), 7.37-7.31 (m, 4H), 7.29 (dt, J=6.3, 0.8 Hz,2H), 7.25-7.15 (m, 2H), 6.04 (d, J=4.0 Hz, 1H), 5.70 (d, J=4.1 Hz, 1H),4.18 (d, J=6.2 Hz, 2H), 1.36 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.82, −121.61; MS (ES+) 607.3 (M+Na); (ES−) 583.2 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(16b)

To a stirred solution of tert-Butyl3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(16a) (0.17 g, 0.291 mmol) in acetonitrile (5 mL) at room temperaturewas added conc. HCl (1.212 mL, 14.54 mmol) and water (1.25 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with 0-100% ethylacetate in hexane) to furnish1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(16c) (0.040 g, 0.080 mmol, 27.6% yield) as a white solid, this wascontaminated by1-(3-(aminomethyl)phenyl)-N-(4-(chloro(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(16d) impurity. Further elution gave1-(3-(Aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(16b) (0.022 g, 0.045 mmol, 15.62% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.34 (s, 3H), 7.71 (d, J=2.0 Hz, 1H),7.67 (s, 1H), 7.59 (td, J=5.4, 2.6 Hz, 1H), 7.55-7.46 (m, 3H), 7.40-7.35(m, 2H), 7.34-7.27 (m, 2H), 7.26-7.16 (m, 3H), 6.07 (d, J=4.0 Hz, 1H),5.71 (d, J=4.0 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −121.23; MS(ES+) 485.1 (M+1); (ES−) 483.2 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17d) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(400 mg, 1.423 mmol) in DMF (10 mL) was addedN₁-phenylbenzene-1,3-diamine (17a) (262 mg, 1.423 mmol),N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48 mmol) andbromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 682mg, 1.434 mmol) followed by stirring at room temperature for 15 h. Thereaction mixture was diluted with ethyl acetate (200 mL), washed withwater (2×75 mL), brine (75 mL), dried, filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to3:1)] to furnish1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17b) (316 mg, 50%) as a brown gum. ¹H NMR (300 MHz, DMSO-d₆) δ 10.57(s, 1H), 8.31-6.73 (m, 14H); MS (ES+) 448.3 (M+1).

Step-2: Preparation of tert-butyl3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(17c)

A solution of1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17b) (200 mg, 0.447 mmol) in methanol (4 mL) was cooled with ice/waterand treated with di-tert-butyl dicarbonate (296 mg, 1.341 mmol) andnickel(II) chloride hexahydrate (21.85 mg, 0.092 mmol) followed byaddition of sodium borohydride (104 mg, 2.68 mmol) slowly over 5 min andstirring at room temperature for 1 h. The reaction mixture was quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.104 mL, 0.952 mmol) followedby stirring at room temperature for 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness. The residue obtained was treated withethyl acetate (100 mL), washed with water (50 mL). The aqueous phase wasextracted again with ethyl acetate (50 mL). The combined extracts werewashed with brine (60 mL), dried over MgSO₄ followed by filtration andconcentration. The crude residue was purified by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to3:1)] to furnish tert-butyl3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(17c) (160 mg, 65%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.63(s, 1H), 8.24 (s, 1H), 7.67-6.51 (m, 14H), 4.20 (d, J=6.3 Hz, 2H), 1.37(s, 9H); MS (ES+) 552.4 (M+1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17d)

To a solution of tert-butyl3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(17c) (127 mg, 0.230 mmol) in 1,4-Dioxane (12 mL) was treated withhydrogen chloride (2.4 mL, 9.60 mmol, 4 M in 1,4-dioxane) dropwisefollowed by stirring at room temperature for 13 h. The reaction mixturewas diluted with hexanes, decanted, washed with hexanes, and decantedagain. The insoluble part was purified by flash column chromatography[silica gel 4 g, eluting with chloroform/CMA80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(17d) (23 mg, 22%) as a white solid, mp: 73.8° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.62 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.48(t, J=2.1 Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.29 (m, 1H), 7.23 (t, J=7.9Hz, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (d, J=2.2 Hz, 2H), 7.05 (s, 1H),6.87-6.78 (m, 2H), 3.78 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.70; MS(ES+) 452.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18g) Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3methanol-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h) Preparationof1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18i) Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18j) Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18k) Step-1: Preparation ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-3H-pyrazole-5-carboxamide(18b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(5.42 g, 19.27 mmol) in DMF (100 mL) was added 3-aminobenzophenone (18a)(3.8 g, 19.27 mmol), N-ethyl-N-isopropylpropan-2-amine (27 mL, 155 mmol)and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop) (9.24g, 19.42 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 39 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (600 mL) washed with water (2×300 mL), brine(200 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-25%] to furnishN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18b) (5.633 g, 63% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.89 (s, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.07-7.98 (m, 3H), 7.93 (ddd,J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.67 (m, 6H), 7.61-7.55 (m, 2H), 7.50 (dt,J=7.7, 1.5 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES+)461.162 (M+1), 483.134 (M+Na).

Step-2: Preparation of tert-butyl3-(5-((3-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c)

To a stirred solution ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18b) (4.704 g, 10.22 mmol) in anhydrous methanol (100 mL), cooled to 0°C., was added di-tert-butyl dicarbonate (6.76 g, 30.7 mmol), nickel(II)chloride hexahydrate (0.5 g, 2.103 mmol) followed by sodium borohydride(2.367 g, 61.3 mmol) portionwise over a 5 mins period. The reactionmixture was stirred for 30 min at room temperature, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (2.3 mL, 21.08 mmol) stirred for 30minutes and concentrated in vacuum to dryness. The residue was dissolvedin ethyl acetate (400 mL), washed with water (200 mL), brine (200 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 80 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (2.71 g, 46.8% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.70 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7.59-7.46 (m, 3H), 7.45-7.40(m, 2H), 7.38-7.25 (m, 7H), 7.23-7.20 (m, 1H), 7.13 (dt, J=7.7, 1.3 Hz,1H), 5.94 (d, J=3.9 Hz, 1H), 5.66 (d, J=3.8 Hz, 1H), 4.19 (d, J=6.2 Hz,2H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80; MS (ES+) 589.3(M+1), (ES−) 565.3 (M−1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (65 mg, 0.115 mmol) in 1,4-Dioxane (6 mL) was added hydrogenchloride (1.2 mL, 4.80 mmol, 4 M in 1,4-dioxane) dropwise and stirred atroom temperature for 13 h. The reaction mixture was diluted with hexanesand decanted. The residue was triturated with hexanes, decanted toobtain1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) as a white solid.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18f)

To a solution of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) in chloroform/methanol (40 mL/15 mL) was added silica gel 2 g andconcentrated in vacuum to obtain a slurry which was purified by flashcolumn chromatography [silica gel 2×4 g, eluting with chloroform/CMA80(1:0 to 2:1)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18f) (26 mgs, 47%) as a white solid, mp: 89.5° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H), 7.65-7.62 (m, 1H), 7.60-7.49 (m, 3H),7.46-7.38 (m, 2H), 7.33 (d, J=4.3 Hz, 5H), 7.31-7.23 (m, 2H), 7.12 (d,J=7.7 Hz, 1H), 5.30 (s, 1H), 3.78 (s, 2H), 3.26 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.74. MS (ES+) 481.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18g)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (193 mg, 0.341 mmol) in 1,4-Dioxane (18 mL) was added hydrogenchloride (3.60 mL, 14.39 mmol, 4 M in 1,4-dioxane) dropwise followed bystirring at room temperature for 21 h. The reaction mixture was dilutedwith hexanes, decanted, and the residue obtained was washed with hexaneswith decantation. To the residue of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) dissolved in chloroform/ethanol (40 mL/15 mL) was added silica gel2 g and concentrated in vacuum to obtain a slurry which was purified byflash column chromatography (silica gel 2×4 g, eluting withchloroform/CMA 80 (1:0 to 2:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18g) as a white solid (24 mg, 14%); ¹H NMR (300 MHz, DMSO-d₆) δ 7.61(s, 1H), 7.57 (s, 2H), 7.52 (s, 1H), 7.42 (d, J=6.2 Hz, 2H), 7.35-7.31(m, 5H), 7.27 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 5.41 (s, 1H),3.76 (s, 2H), 3.47-3.37 (m, 2H), 1.17 (t, J=7.0 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.73. MS (ES+) 495.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18h)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (80 mg, 0.141 mmol) in 1,4-Dioxane (8 mL) was added hydrogenchloride (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) dropwise followed bystirring at room temperature for 16 h. The reaction mixture was dilutedwith hexanes, decanted, and the residue obtained was washed with hexaneswith decantation. To the residue of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) dissolved in chloroform/1-propanol (40 mL/15 mL) was added silicagel 2 g and concentrated in vacuum to obtain a slurry which was purifiedby flash column chromatography (silica gel 2×4 g, eluting withchloroform/CMA 80 (1:0 to 2:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18h) (31 mgs, 43%) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H), 7.61 (t, J=1.8 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.38 (m,2H), 7.36-7.28 (m, 6H), 7.27-7.22 (m, 1H), 7.12 (d, J=7.6 Hz, 1H), 5.39(s, 1H), 3.77 (s, 2H), 3.47-3.39 (m, 2H), 1.64-1.50 (m, 2H), 0.89 (t,J=7.4 Hz, 3H); ¹H NMR (300 MHz, Methanol-d₄) δ 7.57 (t, J=1.9 Hz, 1H),7.53 (s, 1H), 7.52-7.45 (m, 3H), 7.40 (dt, J=4.5, 2.4 Hz, 1H), 7.35-7.22(m, 7H), 7.17-7.11 (m, 1H), 5.34 (s, 1H), 3.86 (s, 2H), 3.40 (td, J=6.4,1.0 Hz, 2H), 1.64 (dtd, J=13.8, 7.4, 6.5 Hz, 2H), 0.95 (t, J=7.4 Hz,3H); ¹⁹F NMR (282 MHz, Methanol-d₄) δ −63.73; MS (ES+): 509.3 (M+1);(ES−) 507.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18i)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (80 mg, 0.141 mmol) in 1,4-Dioxane (8 mL) was added hydrogenchloride (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) dropwise followed bystirring at room temperature for 16 h. The reaction mixture was dilutedwith hexanes, decanted, and the residue obtained was washed with hexaneswith decantation. The residue of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) dissolved in chloroform/iso-butanol (40 mL/15 mL) was added silicagel 2 g and concentrated in vacuum to obtain a slurry which was purifiedby flash column chromatography (silica gel 2×4 g, eluting withchloroform/CMA 80 (1:0 to 2:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18i) (14 mgs, 19%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.59-7.50 (m, 3H), 7.42 (d, J=6.7 Hz,2H), 7.32 (t, J=6.4 Hz, 5H), 7.27-7.21 (m, 1H), 7.12 (d, J=7.7 Hz, 1H),5.38 (s, 1H), 3.77 (s, 2H), 3.20-3.10 (m, 2H), 1.87 (dq, J=13.3, 6.6 Hz,1H), 0.88 (dd, J=6.6, 1.3 Hz, 6H); 19F NMR (282 MHz, DMSO-d₆) δ −60.71;MS (ES+) 523.3 (M+1); (ES−) 521.4 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18j)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (80 mg, 0.141 mmol) in 1,4-Dioxane (8 mL) was added hydrogenchloride (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) dropwise followed bystirring at room temperature for 16 h. The reaction mixture was dilutedwith hexanes, decanted, and the residue obtained was washed with hexaneswith decantation. The residue of1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18d) dissolved in chloroform/1-butanol (40 mL/15 mL) was added silicagel 2 g and concentrated in vacuum to obtain a slurry which was purifiedby flash column chromatography (silica gel 2×4 g, eluting withchloroform/CMA 80 (1:0 to 2:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18j) (14 mgs, 19%) as a colorless semisolid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.72 (s, 1H), 7.64-7.49 (m, 4H), 7.44-7.37 (m, 2H), 7.36-7.20 (m,7H), 7.12 (d, J=8.0 Hz, 1H), 5.39 (s, 1H), 3.77 (s, 2H), 3.43-3.34 (m,2H), 1.54 (dq, J=8.3, 6.3 Hz, 2H), 1.36 (dq, J=9.4, 7.2 Hz, 2H), 0.85(t, J=7.3 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73; MS (ES+): 523.4(M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18k)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (1 g, 1.765 mmol) in 1,4-Dioxane (90 mL) was added a 4 M solutionof hydrogen chloride in dioxane (19.00 mL, 76 mmol). The reactionmixture was stirred at room temperature 16 h and diluted with hexanes.The organic solution was decanted and the residue washed with hexanes.The residue was dissolved in chloroform/cyclopropanemethanol (120 mL/7mL) and stirred at room temperature for 68 h. Silica gel (3 gm) wasadded to the reaction mixture and the mixture was concentrated in vacuumto dryness. The slurry was purified twice by combiflash columnchromatography (silica gel 12 g, eluting with chloroform/CMA80 0-25%) toafford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(18k) (124 mg, 13.5%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H), 7.64-7.50 (m, 4H), 7.46-7.38 (m, 2H), 7.36-7.27 (m, 6H),7.27-7.20 (m, 1H), 7.13 (d, J=7.7 Hz, 1H), 5.44 (s, 1H), 3.77 (s, 2H),3.23 (dd, J=6.7, 1.3 Hz, 2H), 1.14-0.97 (m, 1H), 0.50-0.42 (m, 2H),0.19-0.10 (m, 2H); 19F NMR (300 MHz, DMSO-d₆) δ −60.73; MS (ES+) 521.3(M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19d) Step-1: Preparation ofN-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (400mg, 1.423 mmol) in DMF (10 mL) was added 3-benzylaniline (19a) (261 mg,1.423 mmol), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48 mmol) andbromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 682mg, 1.434 mmol) and stirred at room temperature for 14 h. The reactionmixture was diluted with ethyl acetate (200 mL), washed with water (2×75mL), brine (75 mL), dried over MgSO₄, filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to3:1)] to furnishN-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19b) (330 mg) as a yellow gum, which was used as such for next step; MS(ES+) 469.3 (M+23).

Step-2: Preparation of tert-butyl3-(5-((3-benzylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(19c)

To a solution ofN-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19b) (200 mg, 0.448 mmol) in methanol (4 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (296 mg, 1.344 mmol), nickel(II)chloridehexahydrate (22.00 mg, 0.093 mmol) followed by portion-wise addition ofsodium borohydride (104 mg, 2.69 mmol) over a period of 5 min. Thereaction mixture was stirred at room temperature for 1 h, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.914 mmol), stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was dissolved in ethyl acetate (100 mL), washed with water (50mL). The aqueous phase was extracted again with ethyl acetate (50 mL).The combined extracts were washed with brine (60 mL), dried over MgSO₄,filtered and concentrated in vacuum to dryness. The crude productobtained was purified by flash column chromatography [silica gel 12 g,eluting with hexanes/ethyl acetate (1:0 to 4:1)] to afford tert-butyl3-(5-(3-benzylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(19c) (121 mg, 26% for two steps) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.68 (s, 1H), 7.72-6.87 (m, 15H), 4.19 (d, J=6.4 Hz, 2H),3.91 (s, 2H), 1.37 (s, 9H); MS (ES+) 473.4 (M+23).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19d)

To a solution of tert-butyl3-(5-(3-benzylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(19c) (105 mg, 0.191 mmol) in 1,4-Dioxane (9 mL) was added drop-wisehydrogen chloride (2.0 mL, 8.0 mmol, 4 M in 1,4-dioxane) and stirred atroom temperature for 18 h. The reaction mixture was treated withhexanes, decanted, washed with hexanes, and decanted again. Theinsoluble part was purified by flash column chromatography on [silicagel 4 g, eluting with chloroform/CMA80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(19d) (33 mg, 38%) as an off-white solid; MP 69.9° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.66 (s, 1H), 7.56-7.41 (m, 6H), 7.33-7.25 (m, 4H),7.24-7.17 (m, 3H), 7.01 (d, J=7.6 Hz, 1H), 3.91 (s, 2H), 3.77 (s, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73; MS (ES+) 451.3 (M+1)

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20d) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(400 mg, 1.423 mmol) in DMF (10 mL) was added 3-phenoxyaniline (20a)(263 mg, 1.423 mmol), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 682 mg, 1.434 mmol) and stirred at room temperature for 14 h.The reaction mixture was diluted with ethyl acetate (200 mL), washedwith water (2×75 mL), brine (75 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel, eluting with hexanes/ethyl acetate(1:0 to 3:1)] to afford1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20b) (296 mg, 46%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.73 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H),7.94-7.87 (m, 1H), 7.78-7.64 (m, 2H), 7.51-7.27 (m, 5H), 7.22-7.11 (m,1H), 7.08-6.99 (m, 2H), 6.83-6.78 (m, 1H); MS (ES+) 471.2 (M+23).

Step-2: Preparation of tert-butyl3-(5-((3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(20c)

To a solution of1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20b) (200 mg, 0.446 mmol) in methanol (4 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (295 mg, 1.338 mmol), nickel(II)chloride hexahydrate (22.00 mg, 0.093 mmol) followed by portion wiseaddition of sodium borohydride (103 mg, 2.68 mmol) slowly over a periodof 5 min. The reaction mixture was stirred at room temperature for 1 h,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.912mmol), stirred at room temperature for 0.5 h. and concentrated in vacuumto dryness. The residue was dissolved in ethyl acetate (100 mL), washedwith water (50 mL). The aqueous phase was extracted again with ethylacetate (50 mL). The combined extracts were washed with brine (60 mL),dried over MgSO₄, filtered and concentrated in vacuum to dryness. Thecrude product was purified by flash column chromatography [silica gel 12g, eluting with hexanes/ethyl acetate (1:0 to 3:1)] to afford tert-butyl3-(5-(3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(20c) (173 mg, 70%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.78(s, 1H), 7.57 (s, 1H), 7.53-6.75 (m, 14H), 4.19 (d, J=6.3 Hz, 2H), 1.37(s, 9H); MS (ES+) 475.4 (M+23).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20d)

To a solution of tert-butyl3-(5-(3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(20c) (115 mg, 0.208 mmol) in 1,4-Dioxane (9 mL) was added drop-wisehydrogen chloride (2.2 mL, 8.8 mmol, 4 M in 1,4-dioxane) and stirred atroom temperature for 18 h. The reaction mixture was treated withhexanes, decanted, washed with hexanes, and decanted again. Theinsoluble part was purified by flash column chromatography [silica gel 4g, eluting with chloroform/CMA80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(20d) (70 mg, 74%) as an off-white solid; MP 89.0° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.80 (s, 1H), 7.60 (s, 2H), 7.52-7.48 (m, 2H), 7.46-7.32 (m,6H), 7.16 (t, J=7.4 Hz, 1H), 7.06-7.01 (m, 2H), 6.82-6.77 (m, 1H), 5.71(s, 2H), 3.95 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78; MS (ES+)453.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(21e) Step-1: Preparation of 3-nitro-N-phenylbenzamide (21b)

To a solution of aniline (2.94 mL, 32.2 mmol) in ethyl acetate (30 mL)at room temperature was added triethylamine (5.39 mL, 38.7 mmol)followed by a solution of 3-nitrobenzoyl chloride (5.98 g, 32.2 mmol) inethyl acetate (30 mL). The reaction was stirred at room temperature for20 h and quenched with water (30 mL). The aqueous layer was separatedextracted with ethyl acetate (2×30 mL). The combined organic layers waswashed with brine (30 mL), dried over anhydrous MgSO₄, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 25 g, eluting with ethyl acetatein hexanes from 0-100%) to furnish 3-nitro-N-phenylbenzamide (21b) (2.93g, 12.1 mmol, 37.5% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H, D₂O exchangeable), 8.79 (t, J=2.0 Hz, 1H), 8.43 (dddd,J=12.0, 7.8, 2.1, 1.1 Hz, 2H), 7.85 (t, J=8.0 Hz, 1H), 7.82-7.75 (m,2H), 7.44-7.35 (m, 2H), 7.20-7.10 (m, 1H).

Step-2: Preparation of 3-amino-N-phenylbenzamide (21c)

To a suspension of palladium on carbon (5%) (0.149 g, 1.404 mmol) inethanol (120 mL) was added 3-nitro-N-phenylbenzamide (3.4 g, 14.04 mmol)and hydrogenated at 45 psi in Parr apparatus for 3 h. The reaction wasfiltered through Celite and concentrated in vacuum. The residue wasdried to give compound 3-amino-N-phenylbenzamide (21c) (2.872 g, 13.53mmol, 96% yield) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.09(s, 1H), 7.84-7.71 (m, 2H), 7.43-7.25 (m, 2H), 7.15 (t, J=7.7 Hz, 1H),7.12-7.04 (m, 3H), 6.75 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.35 (s, 2H, D₂Oexchangeable).

Step-3: Preparation of tert-butyl3-(5-((3-(phenylcarbamoyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(21d)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.1 g, 0.26 mmol) in N,N-dimethylformamide (2 mL) was added3-amino-N-phenylbenzamide (0.066 g, 0.311 mmol),N-ethyl-N-isopropylpropan-2-amine (0.362 mL, 2.076 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP, 0.133 g,0.285 mmol) at room temperature. The reaction mixture was stirred at 25°C. for 16 h. The reaction mixture was diluted with water (10 mL)extracted with ethyl acetate (2×20 mL). The organic layers werecombined, washed with water (10 mL) dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to dryness. Theresidue obtained was purified by flash column chromatography (silica gel12 g, eluting with hexanes in ethyl acetate/hexanes from 0-100%) tofurnish tert-butyl3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(21d) (77 mg, 0.133 mmol, 51.2% yield); ¹H NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 10.29 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 7.87 (d, J=7.9 Hz,1H), 7.79-7.69 (m, 3H), 7.65 (s, 1H), 7.56-7.31 (m, 8H), 7.16-7.06 (m,1H), 4.20 (d, J=6.2 Hz, 2H), 1.37 (s, 9H); MS (ES+) 580.3 (M+1), 602.3(M+23), (ES−) 578.3 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(21e)

To a stirred solution of tert-butyl3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(21d) (50 mg, 0.086 mmol) in methanol (5 mL) was added conc hydrochloricacid (0.052 mL, 1.725 mmol) and stirred the reaction overnight.Additional 20 eq. of HCl was added and stirred at reflux for 30 minutes.The reaction mixture was concentrated in vacuum to dryness. The residuewas dried in vacuum overnight suspended in ether (25 mL), heated atreflux for 30 mins and stirred at room temperature overnight. The solidseparated was collected by filtration dried to give1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (21e) (45 mg, 0.081 mmol, 94% yield) as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H, D₂O exchangeable), 10.32 (s,1H, D₂O exchangeable), 8.34 (s, 3H, D₂O exchangeable), 8.23 (t, J=1.9Hz, 1H), 7.92-7.82 (m, 1H), 7.80-7.71 (m, 5H), 7.65-7.47 (m, 4H),7.40-7.30 (m, 2H), 7.15-7.06 (m, 1H), 4.14 (s, 2H); MS (ES+) 480.2(M+1); (ES−) 478.2 (M−1), 514.12 (M+35); Analysis calculated forC₂₅H₂₀F₃N₅O₂(HCl)₂: C, 54.43; H, 4.02; N, 12.72; Found C, 54.59; H,4.55; N, 12.52.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(22b) Step-1: Preparation of tert-butyl3-(5-((3-benzoylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(22a)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (200 mg, 0.519 mmol) in DMF (5 mL) was added(3-aminophenyl)(phenyl)methanone (18a) (102 mg, 0.518 mmol),N-ethyl-N-isopropylpropan-2-amine (0.730 mL, 4.19 mmol),bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 248mg, 0.522 mmol) and stirred at room temperature for 13 h. The reactionmixture was diluted with ethyl acetate (200 mL), washed with water (100,75 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to affordtert-butyl3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(22a) (182 mg, 62%) as a light yellow gum. ¹H NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78-7.28(m, 13H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H); MS (ES+) 587.3 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(22b)

To a solution of tert-butyl3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(22a) (0.15 g, 0.266 mmol) in 1,4-Dioxane (14 mL) was added dropwisehydrogen chloride (2.80 mL, 11.21 mmol, 4 M in 1,4-dioxane) and stirredat room temperature for 17 h. The reaction mixture was diluted withhexanes and the solid obtained was collected by filtration. The lightyellow solid was purified by flash column chromatography on 2×4 g of[silica gel 2×4 g, eluting with chloroform/CMA 80 (1:0 to 2:1)] toafford tert-butyl3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(22b) (75 mg, 61%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.75 (d,J=1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.71-7.65 (m, 1H), 7.61 (s, 1H),7.60 (s, 1H), 7.57 (s, 1H), 7.56-7.52 (m, 2H), 7.51-7.47 (m, 1H),7.45-7.41 (m, 2H), 7.33 (dt, J=5.3, 2.5 Hz, 1H), 3.78 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.75; MS (ES+) 465.2 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23c) Step-1: Preparation of tert-butyl3-(5-((2-fluoro-3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(23b)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (200 mg, 0.519 mmol) in DMF (5 mL) was added2-fluoro-3-phenoxyaniline (23a) (105 mg, 0.519 mmol),N-ethyl-N-isopropylpropan-2-amine (0.730 mL, 4.19 mmol),bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 249mg, 0.523 mmol) and stirred at room temperature for 15 h. The reactionmixture was diluted with ethyl acetate (150 mL), washed with water (2×75mL), brine (750 mL), dried over MgSO₄, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23b) (72 mg, 24%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.80-6.72 (m, 13H), 3.78 (s, 2H); MS (ES+): 593.2 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23c)

To a solution of tert-butyl3-(5-(2-fluoro-3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(23b) (70 mg, 0.123 mmol) in 1,4-Dioxane (5 mL) was added dropwisehydrogen chloride (1.3 mL, 5.2 mmol, 4 M in 1,4-dioxane) and stirred atroom temperature for 16 h. The reaction mixture was diluted with hexanesand the solid obtained was collected by filtration. The light yellowsolid was purified by flash column chromatography on [silica gel 2×4 g,eluting with chloroform/CMA 80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23c) (32 mg, 55%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.60(s, 1H), 7.53 (s, 1H), 7.48-7.32 (m, 6H), 7.24-7.11 (m, 2H), 7.06-6.97(m, 3H), 3.78 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.76, −139.25; MS(ES+), 471.2 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(24c) Step-1: Preparation of tert-butyl3-(5-((2-fluoro-5-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(24b)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (152 mg, 0.394 mmol) in DMF (3.5 mL) was treated with2-fluoro-5-phenoxyaniline (24a) (80 mg, 0.394 mmol),N-ethyl-N-isopropylpropan-2-amine (0.550 mL, 3.16 mmol)bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 189mg, 0.398 mmol) and stirred at room temperature for 15 h. The reactionmixture was diluted with ethyl acetate (100 mL), washed with water (2×50mL), brine (50 mL), dried over MgSO₄, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 3:1)] to affordtert-butyl3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(24b) (57 mg, 25%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65(s, 1H), 7.58 (s, 1H), 7.53-6.86 (m, 13H), 4.18 (d, J=6.3 Hz, 2H), 1.37(s, 9H); (ES+) 593.3 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(24c)

To a solution of tert-butyl3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(24b) (55 mg, 0.096 mmol) in 1,4-Dioxane (4 mL) was added dropwisehydrogen chloride (1.0 mL, 4.0 mmol, 4 M in 1,4-dioxane) and stirred atroom temperature for 16 h. The reaction mixture was diluted with hexanesand the solid obtained was collected by filtration. The solid obtainedwas purified by flash column chromatography [silica gel 4 g, elutingwith chloroform/CMA 80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(24c) (20 mg, 44%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68(s, 1H), 7.65-7.55 (m, 2H), 7.52-7.30 (m, 7H), 7.15 (tt, J=6.9, 1.2 Hz,1H), 7.03-6.98 (m, 2H), 6.96-6.89 (m, 1H), 3.95 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.80, −127.85; MS (ES+) 471.2 (M+1); (ES−) 469.1 (M−1)

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25b) and1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25c) Step-1: Preparation of tert-butyl3-(5-((2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(25a)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (284 mg, 0.737 mmol) in DMF (6.5 mL) was added(3-amino-4-fluorophenyl)(phenyl)methanol (26c) (160 mg, 0.737 mmol),N-ethyl-N-isopropylpropan-2-amine (1.05 mL, 6.03 mmol)bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 353mg, 0.742 mmol) and stirred at room temperature for 12 h. The reactionmixture was diluted with ethyl acetate (150 mL), washed with water (2×75mL), brine (60 mL), dried over MgSO₄, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 1:1)] to affordtert-butyl3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(25a) (196 mg, 46%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.56(s, 1H), 7.64-7.14 (m, 14H), 6.00 (d, J=3.9 Hz, 1H), 5.69 (d, J=4.0 Hz,1H), 4.19 (d, J=6.2 Hz, 2H), 1.38 (s, 9H); MS (ES+) 607.3 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25b) and1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25c)

To a solution of tert-butyl3-(5-((2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(25a) (0.18 g, 0.308 mmol) in 1,4-Dioxane (16 mL) was added dropwisehydrogen chloride (3.2 mL, 12.81 mmol, 4 M in 1,4-dioxane) and stirredat room temperature for 26 h. The reaction mixture was diluted withhexanes (˜80 mL) and decanted to obtain yellow oil. Part of theinsoluble yellow oil was dissolved in ethanol and converted to a silicagel slurry. The slurry was purified by flash column chromatography[silica gel 4 g, eluting with chloroform/CMA 80 (1:0 to 3:1)] to afford1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25b) (61 mg, 39%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.57(s, 1H), 7.54 (d, J=18.4 Hz, 3H), 7.45-7.38 (m, 2H), 7.33 (M, 5H),7.27-7.22 (m, 3H), 5.45 (s, 1H), 3.77 (s, 2H), 3.42 (q, J=7.0 Hz, 2H),1.16 (t, J=7.0 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.76, −122.95; MS(ES+) 513.3 (M+1); (ES−) 511.2 (M−1).

Another part of the insoluble yellow oil was dissolved in methanol andconverted to silica gel The slurry was purified by flash columnchromatography [silica gel 4 g, eluting with chloroform/CMA 80 (1:0 to1:1)] to afford1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(25c) (11 mg, 7.2%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.58(s, 1H), 7.61-7.52 (m, 3H), 7.52-7.34 (m, 2H), 7.40-7.29 (m, 6H),7.29-7.21 (m, 4H), 5.34 (s, 1H), 3.80 (s, 2H), 3.25 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.77, −122.99; MS (ES+) 499.3 (M+1); (ES−) 497.3(M−1); 533.3 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(26f) Step-1: Preparation of (4-fluoro-3-nitrophenyl)(phenyl)methanol(26b)

To a solution of 4-fluoro-3-nitrobenzaldehyde (26a) (4 g, 23.65 mmol) inTHF (60 mL) cooled to 0° C. was added dropwise phenylmagnesium bromide(48.0 mL, 48.0 mmol) and stirred at room temperature for 14 h. Thereaction mixture was quenched with saturated aqueous NH₄Cl (240 mL),extracted with ethyl acetate (300 mL, 150 mL). The combined extractswere washed with brine (150 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel 80 g, eluting with hexanes/ethyl acetate (1:0to 2:1)] to afford (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (3.265g, 56%) as a brown gum. ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.24(s, 1H), 7.67-6.51 (m, 14H), 4.20 (d, J=6.3 Hz, 2H), 1.37 (s, 9H); MS(ES+) 270.1 (M+1).

Step-2: Preparation of (3-amino-4-fluorophenyl)(phenyl)methanol (26c)and 5-benzyl-2-fluoroaniline (26d)

A solution of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (2 g, 8.09mmol) in ethanol (70 mL) and ethyl acetate (35 mL) was added Pd/C 10%(0.440 g, 0.413 mmol) followed by hydrogenation (˜50 Psi) for 4.5 h. Thereaction mixture was filtered through a pad of Celite and the filtratewas treated with 4 M HCl in 1,4-dioxane (˜0.2 mL) and 4 N HCl (aq., ˜0.2mL) to pH=˜5. The filtrate was concentrated in vacuum and the residueobtained was purified by flash column chromatography [silica gel 25 g,eluting with hexanes/ethyl acetate (1:0 to 3:1)] to afford

-   -   1. (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (175 mg, 10%)        as a light brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37-7.14 (m,        5H), 6.87 (dd, J=11.5, 8.3 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz,        1H), 6.50 (176 dd, J=8.3, 4.6, 2.2, 0.6 Hz, 1H), 5.75 (d, J=3.9        Hz, 1H), 5.52 (d, J=3.9 Hz, 1H), 5.06 (s, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −137.89; MS (ES+): 218.2 (M+1).    -   2. 5-benzyl-2-fluoroaniline (26d) (1.084 g, 67%) as a brown gum;        ¹H NMR (300 MHz, DMSO-d₆) δ 7.34-7.11 (m, 5H), 6.86 (dd, J=11.6,        8.2 Hz, 1H), 6.57 (dd, J=8.9, 2.2 Hz, 1H), 6.36 (ddd, J=8.2,        4.5, 2.2 Hz, 1H), 5.04 (s, 2H), 3.76 (s, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −139.01; MS (ES+): 202.1 (M+1).

Step-3: Preparation of tert-butyl3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(26e)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (303 mg, 0.786 mmol) in DMF (7 mL) was added5-benzyl-2-fluoroaniline (26d) (158 mg, 0.786 mmol),N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 6.31 mmol)bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 377mg, 0.793 mmol) and stirred at room temperature for 19 h. The reactionmixture was diluted with ethyl acetate (150 mL), washed with water (2×75mL), brine (60 mL), dried over MgSO₄, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 3:1)] to affordtert-butyl3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(26e)(228 mg) as a white solid, which was used as such for next step; MS(ES+) 591.3 (M+23);

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(26f)

To a solution of tert-butyl3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(26e) (0.202 g, 0.355 mmol) in 1,4-Dioxane (18 mL) was added dropwisehydrogen chloride (3.7 mL, 14.78 mmol, 4 M in 1,4-dioxane) and stirredat room temperature for 21 h. The reaction mixture was diluted withhexanes and the yellow solid obtained was collected by filtration. Theyellow solid was purified by flash column chromatography [silica gel 12g, eluting with chloroform/methanol (1:0 to 9:1)] to afford1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(26f) (99 mg) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s,1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.47-7.40 (m, 3H), 7.35-7.25 (m, 3H),7.27-7.15 (m, 4H), 7.13 (ddt, J=8.5, 5.0, 2.2 Hz, 1H), 3.92 (s, 2H),3.78 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −125.06; MS (ES+)469.3 (M+1); (ES−) 467.2 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(27f) Step-1: Preparation of 3-nitro-N-phenyl-N-propylaniline (27c)

To a solution of 1-bromo-3-nitrobenzene (27a) (3 g, 14.85 mmol) andN-propylaniline (27b) (2.41 g, 17.82 mmol) in toluene (15 mL) was addedsodium 2-methylpropan-2-olate (1.142 g, 11.88 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.859 g,1.485 mmol) and Tris(dibenzylideneacetone)dipalladium (0) (0.408 g,0.446 mmol). The reaction mixture was stirred at 110° C. for 16 h undera positive flow of nitrogen. Reaction mixture was cooled to roomtemperature, quenched with water (75 mL), extracted with ethyl acetate(2×100 mL). The organic layers were combined dried over MgSO₄, filteredand evaporated to dryness. The residue obtained was purified by flashcolumn chromatography [(silica gel 80 g, eluting with ethyl acetate inhexanes from 0 to 100%)] to afford 3-nitro-N-phenyl-N-propylaniline(27c) (2.931 g, 11.44 mmol, 77% yield) as a brown-yellow oil. Isolatedproduct was not very pure but good enough to be used as such for nextstep; MS (ES+) 257.2 (M+1).

Step-2: Preparation of N₁-phenyl-N₁-propylbenzene-1,3-diamine (27d)

To a solution of 3-nitro-N-phenyl-N-propylaniline (27c) (2.9 g, 11.31mmol) in methanol (30 mL) was added palladium (10% Pd on carbon, 0.241g). The mixture was hydrogenated for 2 h, filtered through a pad ofCelite and the filtrate was concentrated in vacuum to dryness. Theresidue was purified by flash column chromatography (silica gel 80 g,eluting with ethyl acetate in hexanes from 0 to 100%) to affordN₁-phenyl-N₁-propylbenzene-1,3-diamine (27d) (1.195 g, 5.28 mmol, 46.7%yield) as a dark-green oil; MS (ES+) 227.2 (M+1).

Step-3: Preparation of tert-butyl3-(5-((3-(phenyl(propyl)amino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(27e)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.19 g, 0.493 mmol) in DMF (3 mL) was addedN₁-phenyl-N₁-propylbenzene-1,3-diamine (27d) (0.134 g, 0.592 mmol),N-ethyl-N-isopropylpropan-2-amine (0.687 mL, 3.94 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop, 0.253 g,0.542 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 17 h and concentrated in vacuum to dryness. Thereaction was diluted with water (25 mL) and extracted with ethyl acetate(50, 20 mL). The organic layers were combined, dried, filtered, andevaporated to dryness. The residue obtained was purified by flash columnchromatography [silica gel 12 g, eluting with ethyl acetate in hexanesfrom 0-25%] to afford tert-butyl3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(27e) (0.199 g, 0.335 mmol, 68.0% yield) as a white solid; MS (ES+)616.3 (M+Na), (ES−) 592.3 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(27f)

To a solution of tert-butyl3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(27e) (0.183 g, 0.308 mmol) in dioxane (4 mL) was added drop-wisehydrogen chloride (4M in dioxane, 4.32 mL, 17.26 mmol) and stirred atroom temperature for 15 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was purified by flash columnchromatography (silica gel 25 g, eluting with methanol in chloroformfrom 0-100%) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(27f) (0.086 g, 0.174 mmol, 56.5% yield) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H, D₂O exchangeable), 7.53 (s,2H), 7.49-7.42 (m, 2H), 7.34-7.23 (m, 4H), 7.22-7.17 (m, 2H), 7.05-6.93(m, 3H), 6.71-6.67 (m, 1H), 3.81 (s, 2H), 3.68-3.54 (m, 2H), 1.57 (h,J=7.5 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.73; MS (ES+) 494.3 (M+1), (ES−) 492.2 (M−1), 528.2 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(28f) Step-1: Preparation of N-methyl-N-(3-nitrobenzyl)aniline (28c)

To a solution of 1-(chloromethyl)-3-nitrobenzene (28a) (4 g, 23.31 mmol)in DMF (50 mL) was added N-methylaniline (28b) (2.53 mL, 23.31 mmol)followed by potassium carbonate (20.94 g, 152 mmol). The reactionmixture stirred at room temperature for 20 h, poured into water (200 mL)and extracted with ethyl acetate (2×50 mL). The organic layers werecombined washed with water (100 mL), brine (50 mL), dried, filtered andconcentrated in vacuum to furnish crude product. The crude was purifiedby flash column chromatography (silica gel 40 gm eluting with 0-100%ethyl acetate in hexane) to furnish N-methyl-N-(3-nitrobenzyl)aniline(28c) which was pure enough to be used for next step; MS (ES+) 243.2(M+1).

Step-2: Preparation of N-(3-aminobenzyl)-N-methylaniline (28d)

To a stirred solution of N-methyl-N-(3-nitrobenzyl)aniline (28c) (1.5 g,6.19 mmol) in acetic acid (20 mL) was added iron powder (1.729 g, 31.0mmol), heated to 60° C. and stirred for 30 minutes. The reaction wasquenched by adding water (100 mL) and filtered. The filtrate wasextracted with ethyl acetate (2×100 mL). The ethyl acetate layers werecombined, washed with water (2×100 mL), brine (50 mL) dried andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography to afford N-(3-aminobenzyl)-N-methylaniline (28d)(533 mg, 2.51 mmol, 40.6% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 7.19-7.06(m, 2H), 7.02-6.92 (m, 1H), 6.73-6.64 (m, 2H), 6.58 (tt, J=7.2, 1.0 Hz,1H), 6.49-6.36 (m, 3H), 5.46 (s, 2H, D₂O exchangeable), 4.39 (s, 2H),2.98 (s, 3H); MS (ES+) 213.2 (M+1).

Step-3: Preparation of tert-butyl3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(28e)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (193 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.697 mL, 4.00 mmol),N-ethyl-N-isopropylpropan-2-amine (0.697 mL, 4.00 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP, 256 mg,0.55 mmol) at room temperature. The reaction mixture was stirred at 25°C. for 16 h, diluted with water (20 mL) and extracted with ethyl acetate(2×50 mL). The organic layers were combined dried over anhydrous MgSO₄,filtered, concentrated under reduced pressure to dryness. The residueobtained was purified by flash column chromatography (silica gel 12g,eluting with hexanes in ethyl acetate/hexanes 0-100%) to furnishtert-butyl3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(28e) (110 mg, 0.190 mmol, 37.9% yield) as colorless sticky material; ¹HNMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H, D₂O exchangeable), 7.59-7.45 (m,4H), 7.45-7.38 (m, 2H), 7.34 (d, J=7.7 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H),7.20-7.07 (m, 2H), 6.97 (d, J=7.7 Hz, 1H), 6.69 (d, J=8.1 Hz, 2H), 6.60(t, J=7.2 Hz, 1H), 4.52 (s, 2H), 4.19 (d, J=6.2 Hz, 2H), 3.01 (s, 3H),1.37 (s, 9H); MS (ES+) 580.4 (M+1), 602.4 (M+23), (ES−) 578.4 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(28f)

To a stirred solution of tert-butyl3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(28e) (100 mg, 0.173 mmol) in methanol (10 mL) was added HCl (0.575 mL,6.90 mmol) and stirred at room temperature overnight. The reaction washeated to reflux for 30 mins and concentrated in vacuum to dryness. Theresidue was dried in vacuum overnight, suspended in ether (25 mL),heated for 30 mins and stirred at room temperature overnight. The solidseparated was collected by filtration dried to give1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (28f) (75 mg, 0.145 mmol, 84% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.38 (s, 3H), 7.72 (s, 1H),7.66 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.58-7.54 (m, 1H), 7.54-7.47 (m,2H), 7.28 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.7 Hz, 2H), 7.00 (d, J=7.5 Hz,1H), 6.70 (d, J=25.7 Hz, 3H), 4.54 (s, 2H), 4.13 (d, J=5.7 Hz, 3H), 3.02(s, 3H); MS (ES+) 480.3 (M+1); (ES−) 478.2 (M−1), 514.2 (M+35).

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(29e) Step-1: Preparation of 2-fluoro-3-nitro-N-phenyl-N-propylaniline(29b)

To a solution of 1-bromo-2-fluoro-3-nitrobenzene (29a) (3 g, 13.64 mmol)and N-propylaniline (27b) (2.213 g, 16.36 mmol) in toluene (80 mL) wasadded sodium 2-methylpropan-2-olate (1.048 g, 10.91 mmol),biphenyl-2-yldi-tert-butylphosphine (0.407 g, 1.364 mmol) andTris(dibenzylideneacetone)dipalladium (0) (0.375 g, 0.409 mmol). Thereaction mixture was stirred at 110° C. for 16 h under a positive flowof nitrogen. Reaction was quenched with water (75 mL), extracted withethyl acetate (2×100 mL). The combined organics were dried over MgSO₄,filtered, evaporated to dryness. The residue was purified by flashcolumn chromatography (silica gel 80 g, eluting with ethyl acetate inhexanes from 0 to 100%) to afford2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b) (3.451 g, 12.58 mmol,92% yield) as a brown-yellow oil; which was pure enough to be taken tonext step; MS (ES+) 275.2 (M+1).

Step-2: Preparation of 2-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine(29c)

To a solution of 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b) (3.4 g,12.40 mmol) in methanol (30 mL) was added palladium (10% Pd on carbon,0.264 g, 2.479 mmol). The mixture was hydrogenated for 2.5 h, filteredthrough a pad of Celite and concentrated to dryness. The residue waspurified by flash column chromatography (silica gel 80 g, eluting withethyl acetate in hexanes from 0 to 100%) to afford2-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine (29c) (0.295 g, 1.207mmol, 9.74% yield) as a brown oil; MS (ES+) 245.2 (M+1); (ES−) 243.2(M−1).

Step-3: Preparation of tert-butyl3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(29d)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.190 g, 0.493 mmol) in N,N-dimethylformamide (2.98 mL, 38.5mmol) was added 2-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine (29c)(0.145 g, 0.592 mmol), N-ethyl-N-isopropylpropan-2-amine (0.687 mL, 3.94mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP,0.253 g, 0.542 mmol) at room temperature. The resulting reaction mixturewas stirred at 25° C. for 17 h. Excess DMF was pumped-off under reducedpressure. The reaction mixture was extracted with ethyl acetate (50 mL,20 mL). The organic layers were combined dried over anhydrous MgSO₄,filtered, concentrated under reduced pressure to dryness. The residuewas purified by flash column chromatography (silica gel 120 g, elutingwith hexanes in ethyl acetate/hexanes from 0-100%) to furnish tert-butyl3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(29d) (0.182 g, 0.298 mmol, 60.3% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 7.57 (s,1H), 7.53-7.31 (m, 4H), 7.28-7.15 (m, 4H), 6.94-6.83 (m, 4H), 4.18 (d,J=6.2 Hz, 2H), 3.68-3.51 (m, 2H), 1.55 (q, J=7.5 Hz, 2H), 1.37 (s, 9H),0.87 (t, J=7.4 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −129.49; MS(ES+) 634.33 (M+Na), MS (ES−) 610.31 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(29e)

To a solution of tert-butyl3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(29d) (0.166 g, 0.271 mmol) in dioxane (4 mL) was added drop-wisehydrogen chloride (4 N in dioxane) (3.80 mL, 15.20 mmol) and stirred atroom temperature for 15 h. TLC analysis (CHCl₃/MeOH, 8/2, v/v) showsreaction was complete. Excess solvent was pumped-off under reducedpressure, the residue was purified by flash column chromatography(silica gel 25 g, eluting with methanol in chloroform 0-100%) to furnish1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(29e) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.57 (s, 1H), 7.52 (s, 1H), 7.48-7.40 (m,2H), 7.37-7.30 (m, 1H), 7.29-7.16 (m, 4H), 6.95-6.82 (m, 4H), 3.79 (s,2H), 3.65-3.51 (m, 2H), 1.54 (h, J=7.3 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −129.55; MS (ES+): MS (ES+) 512.3(M+1), (ES−) 510.3 (M−1), 546.2 (M+Cl).

Preparation ofN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30g) Step-1: Preparation of (3-amino-4-fluorophenyl)methanol (30b)

To a solution of (4-fluoro-3-nitrophenyl)methanol (30a) (3.81 g, 22.24mmol) in methanol (30 mL) was added palladium on carbon (10%) (0.39 g,3.67 mmol) and hydrogenated at 60 PSI for 1 h. The catalyst was removedby filtration through Celite and the filtrate was concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel 40 g, eluting with 0-100% ethyl acetate/methanol (9:1) inhexanes] to furnish (3-amino-4-fluorophenyl)methanol (30b) (3.05 g,21.61 mmol, 97% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ6.89 (dd, J=11.6, 8.2 Hz, 1H), 6.73 (dd, J=9.1, 2.1 Hz, 1H), 6.52-6.33(m, 1H), 5.20-4.91 (m, 3H), 4.32 (dd, J=5.8, 0.9 Hz, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −138.13.

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(5.67 g, 20.15 mmol) in DMF (50 mL) was added(3-amino-4-fluorophenyl)methanol (30b) (2.37 g, 16.79 mmol),N-ethyl-N-isopropylpropan-2-amine (14.62 mL, 84 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop) (8.61 g,18.47 mmol) at room temperature. The resulting reaction mixture wasstirred at room temperature for 16 h under nitrogen atmosphere. Thereaction mixture diluted with water (25 mL) was extracted with ethylacetate (2×50 mL), washed with brine (25 mL), the combined organic layerwas dried over anhydrous MgSO₄, filtered, and evaporated to dryness. Theresidue obtained was purified by flash column chromatography [silica gel40 g, eluting with 0-100% ethyl acetate/methanol (9/1) in hexanes] tofurnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30c) (1.66 g, 4.11 mmol, 24.45% yield) as a white solid; ¹HNMR (300MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.18-8.09 (m, 1H), 8.00 (dt, J=7.8, 1.3Hz, 1H), 7.91 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 7.78-7.69 (m, 2H),7.57-7.45 (m, 1H), 7.33-7.15 (m, 2H), 5.30 (t, J=5.7 Hz, 1H), 4.46 (d,J=5.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98, −124.32; MS (ES+)427.2 (M+Na), (ES−) 403.2 (M−1).

Step-3: Preparation ofN-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30d)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30c) (1.66 g, 4.11 mmol) in dichloromethane (30 mL) was added at 0° C.thionyl chloride (1.798 mL, 24.63 mmol) and stirred for 2.5 h. Thereaction mixture was concentrated in vacuo to give a white residue.Residue was dissolved in CHCl₃ and treated with silica gel (2 g). Theslurry obtained was purified by flash column chromatography (silica gel40 g, eluting with ethyl acetate in hexanes from 0-50%) to furnishN-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30d) (1.353 g, 78% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.63 (s, 1H), 8.18-8.11 (m, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H), 7.91(ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.80-7.65 (m, 3H), 7.43-7.22 (m, 2H),4.77 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98 (d, J=6.8 Hz),−121.36.

Step-4: Preparation ofN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30e)

To a stirred solution ofN-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30d) (0.15 g, 0.355 mmol) in N,N-dimethylformamide (4 mL) was addedimidazole (0.121 g, 1.774 mmol) and potassium carbonate (0.343 g, 2.484mmol) and stirred at room temperature for 5 days. The reaction wasconcentrated in vacuum and the residue obtained was dissolved inmethanol and filtered through a Celite® pad. The filtrate was evaporatedto dryness and the crude residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% methanol inchloroform) to furnishN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30e) (0.107 g, 66.4% yield) as white foamy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.59 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.94-7.86 (m, 1H), 7.77-7.71 (m, 3H), 7.43 (d, J=7.1 Hz, 1H),7.31 (dd, J=10.4, 8.5 Hz, 1H), 7.23-7.14 (m, 2H), 6.90 (t, J=1.1 Hz,1H), 5.19 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98 (d, J=5.4 Hz),−122.18; MS (ES+) 455.2 (M+1), (ES−) 453.2 (M−1).

Step-5: Preparation of tert-butyl3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(30f)

To a stirred solution ofN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30e) (0.1 g, 0.22 mmol) in anhydrous methanol (10 mL), cooled to 0° C.,were added, di-tert-butyl dicarbonate [(Boc)₂O)](0.144 g, 0.66 mmol),nickel(II) chloride hexahydrate (10.46 mg, 0.044 mmol), sodiumborohydride (0.050 g, 1.320 mmol) was then added in small portions over5 min. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.048 mL, 0.440 mmol) stirred atroom temperature 30 minutes and concentrated in vacuum to dryness. Theresidue was dissolved in water/ethyl acetate (1:1 25 mL each. Theorganic layer was separated and concentrated in vacuum to dryness, theresidue obtained was purified by flash column chromatography (silica gel12 g, eluting with 0 to 50% ethyl acetate/hexanes) to furnish tert-butyl3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(30f) (0.042 g, 0.075 mmol, 34.2% yield) as a white solid; MS (ES+)559.3 (M+1), (ES−) 557.2 (M−1).

Step-6: Preparation ofN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30g)

To a solution of tert-butyl3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(30f) (0.022 g, 0.039 mmol) in dioxane (4 mL) was added hydrogenchloride (4 N in dioxane, 0.551 mL, 2.206 mmol) drop-wise and stirred atroom temperature for 15 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% methanol inchloroform) to furnishN-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(30g) (0.016 g, 0.035 mmol, 89% yield) as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 14.58 (s, 1H, D₂O exchangeable), 10.77 (s, 1H, D₂Oexchangeable), 9.21 (s, 1H), 8.37 (s, 3H, D₂O exchangeable), 7.75 (t,J=1.6 Hz, 1H), 7.69 (ddd, J=11.3, 3.6, 1.7 Hz, 4H), 7.64-7.54 (m, 2H),7.54-7.48 (m, 1H), 7.40-7.33 (m, 2H), 5.42 (s, 2H), 4.12 (d, J=5.7 Hz,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −121.10; MS (ES+): MS (ES+)459.3 (M+1), (ES−) 457.3 (M−1), 493.2 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(31f) Step-1: Preparation of (3-Nitrophenyl)(pyridin-3-yl)methanol (31c)

To a solution of 3-bromopyridine (31b) (2.89 mL, 30.0 mmol) in ether (20mL) at −78° C. was added dropwise n-BuLi (15.94 mL, 25.5 mmol) andstirred for 30 mins at −78° C. To the 3-lithiated pyridine was addeddropwise a solution of 3-nitrobenzaldehyde (31a) (4.53 g, 30 mmol) inTHF (30 mL) at −78° C. and stirred at −78° C. for 2 h and at roomtemperature for 2 h.

The reaction mixture was quenched with saturated ammonium chloride (50mL). The organic layer was separated, dried, filtered and concentratedin vacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel 80 g, eluting with 0-100% ethyl acetate inhexane) to afford (3-Nitrophenyl)(pyridin-3-yl)methanol (31c) (2.842 g,12.34 mmol, 41.1% yield) as a yellow solid.

1H NMR (300 MHz, DMSO-d₆) δ 8.66 (d, J=2.2 Hz, 1H), 8.47 (dd, J=4.8, 1.7Hz, 1H), 8.30 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8.2, 2.5, 1.1 Hz, 1H),7.85 (d, J=7.5 Hz, 1H), 7.78 (dt, J=7.9, 2.0 Hz, 1H), 7.64 (t, J=7.9 Hz,1H), 7.36 (ddd, J=7.9, 4.7, 0.9 Hz, 1H), 6.45 (d, J=4.2 Hz, 1H), 5.99(d, J=4.0 Hz, 1H); MS (ES+) 231.1 (M+1), (ES−) 459.4 (2M−1).

Step-2: Preparation of (3-aminophenyl)(pyridin-3-yl)methanol (31d)

To a solution of (3-nitrophenyl)(pyridin-3-yl)methanol (31c) (1 g, 4.34mmol) in ethanol (36 mL) and ethyl acetate (18 mL) was added Pd/C 10%(0.1 g) and hydrogenated at ˜50 Psi for 2 h. The reaction mixture wasfiltered through a pad of Celite and filtrate was concentrated in vacuo.The crude product was purified by flash column chromatography [silicagel 2×12 g, eluting with chloroform/methanol (1:0 to 9:1)] to afford(3-aminophenyl)(pyridin-3-yl)methanol (31d) (209 mg, 24%) as a yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (dt, J=2.2, 0.7 Hz, 1H), 8.40(dd, J=4.8, 1.7 Hz, 1H), 7.68 (dddd, J=7.8, 2.3, 1.7, 0.6 Hz, 1H), 7.31(ddd, J=7.8, 4.7, 0.9 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.61-6.56 (m,1H), 6.55-6.48 (m, 1H), 6.40 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.89 (d,J=3.9 Hz, 1H), 5.58 (d, J=3.9 Hz, 1H), 5.05 (s, 2H); MS (ES+) 201.1(M+1).

Step-3: Preparation of tert-butyl3-(5-(3-(hydroxy(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(31e)

To a solution of (3-aminophenyl)(pyridin-3-yl)methanol (31d) (80 mg,0.400 mmol) in N,N-dimethylformamide (4 mL) was added1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (154 mg, 0.400 mmol), N-ethyl-N-isopropylpropan-2-amine(0.560 mL, 3.22 mmol) and bromotripyrrolidin-1-ylphosphoniumhexafluorophosphate (V) (PyBroP, 192 mg, 0.403 mmol) at roomtemperature. The reaction mixture was stirred at 25° C. for 22 h anddiluted with ethyl acetate (120 mL). The reaction mixture was washedwith water (2×60 mL), brine (60 mL), dried over anhydrous MgSO₄,filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography [silica gel 12 g, eluting withchloroform/methanol (1:0 to 9:1)] to furnish tert-butyl3-(5-(3-(hydroxy(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(31e) (153 mg, 68%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1.7 Hz, 1H), 7.70 (dt,J=8.1, 2.1 Hz, 1H), 7.64 (t, J=1.9 Hz, 1H), 7.60-7.11 (m, 10H), 6.14 (d,J=4.0 Hz, 1H), 5.76 (d, J=4.0 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s,9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80; MS (ES+) 568.3 (M+1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(31f)

To a stirred solution of tert-butyl3-(5-(3-(hydroxy(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(31e) (135 mg, 0.238 mmol) in 1,4-Dioxane (12 mL) was added 4 M HCl indioxane (2.5 mL, 10.0 mmol) and stirred at room temperature for 17 h.The reaction was diluted with hexanes and decanted. The residue waswashed with hexanes, and decanted again. The insoluble product wasdissolved in chloroform (40 mL)/ethanol (10.00 mL) and converted to aslurry with 2 g of silica gel. The slurry was purified by flash columnchromatography [silica gel, eluting with chloroform/CMA 80 (1:0 to 1:1)]to afford1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(31f) (93 mg, 84%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70(s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1.7 Hz, 1H), 7.70 (dt,J=8.0, 2.0 Hz, 1H), 7.66 (t, J=1.8 Hz, 1H), 7.56 (d, J=3.2 Hz, 1H),7.55-7.49 (m, 2H), 7.46-7.38 (m, 2H), 7.37-7.26 (m, 3H), 7.16 (d, J=7.6Hz, 1H), 6.15 (d, J=4.0 Hz, 1H), 5.76 (s, 1H), 3.77 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.73; MS (ES+) 468.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32f) Step 1: Preparation of 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a)

To a stirred solution of (3-aminophenyl)(phenyl)methanone (18a) (2 g,10.14 mmol) in tetrahydrofuran (40 mL) was added n-BuLi (19.01 mL, 30.4mmol, 1.6 M in hexanes) at 0° C. The reaction was allowed to warm toroom temperature overnight, quenched by adding ammonium chloridesolution (50 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried, filtered and concentrated in vacuum to dryness. The crude residueof 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a) was used as such in nextstep without further purification; MS (ES−) 254.1 (M−1).

Step 2: Preparation of 3-(1-phenylpentyl)aniline (32b) and(Z)-3-(1-phenylpent-1-en-1-yl)aniline (32c)

To the solution of 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a) (0.7 g,2.74 mmol) in dichloromethane (10 mL) was added at 0° C. borontrifluoride etherate (0.695 mL, 5.48 mmol), triethylsilane (1.751 mL,10.97 mmol) and stirred at room temperature overnight. The reactionmixture was quenched by adding ammonium chloride solution and extractedwith dichloromethane (2×50 mL). The organic layers were combined washedwith water, brine, dried, filtered and concentrated in vacuum. Theresidue was purified by flash column chromatography to afford compoundcontaining a inseparable mixture of 3-(1-phenylpentyl)aniline (32b) and(Z)-3-(1-phenylpent-1-enyl)aniline (32c). This mixture was used as suchfor next step; MS (ES+) 238.2 (M+1) (32c) and 240.2 (M+1, 32b), (ES−)239.1 (M−1, 32b).

Step 3: Preparation of pure 3-(1-phenylpentyl)aniline (32b)

To a suspension of Pd—C (10% on carbon) (10.76 mg, 0.101 mmol) inmethanol (30 mL) was added a mixture of 3-(1-phenylpentyl)aniline (32b)and (Z)-3-(1-phenylpent-1-enyl)aniline (32c) (240 mg, 1.011 mmol) andhydrogenated at 60 psi for 3 h. The reaction mixture was filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography to furnish 3-(1-phenylpentyl)aniline (155 mg, 0.648 mmol,64.0% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.25 (d, J=4.9 Hz,4H), 7.18-7.09 (m, 1H), 6.89 (t, J=7.7 Hz, 1H), 6.49-6.41 (m, 2H), 6.34(ddd, J=7.9, 2.2, 1.0 Hz, 1H), 4.96 (s, 2H), 3.69 (t, J=7.8 Hz, 1H),2.00-1.86 (m, 2H), 1.37-1.22 (m, 2H), 1.22-1.05 (m, 2H), 0.82 (t, J=7.2Hz, 3H); MS (ES+) 240.2 (M+1).

Step 4: Preparation of1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32d)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(147 mg, 0.522 mmol) in N,N-dimethylformamide (3.16 mL, 40.8 mmol) wasadded a solution of 3-(1-phenylpentyl)aniline (32b) (150 mg, 0.627 mmol)in N,N-dimethylformamide (3.16 mL, 40.8 mmol), Bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBroP, 268 mg, 0.575 mmol) at roomtemperature. The reaction mixture was stirred at 25° C. for 16 h andquenched with water (25 mL). The reaction mixture was extracted withethyl acetate (100 mL, 50 mL) and the combined organic layers were driedover anhydrous MgSO₄, filtered, concentrated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography (silica gel12 g, eluting with hexanes in ethyl acetate/hexanes from 0-20%) toafford1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32d) (155 mg, 0.308 mmol, 59.0% yield) as an oil; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3Hz, 1H), 7.90 (ddd, J=8.1, 2.3, 1.2 Hz, 1H), 7.77-7.68 (m, 2H),7.55-7.48 (m, 2H), 7.32-7.22 (m, 5H), 7.21-7.13 (m, 1H), 7.12-7.06 (m,1H), 3.88 (t, J=7.8 Hz, 1H), 1.95 (d, J=8.0 Hz, 2H), 1.36-1.25 (m, 2H),1.16 (d, J=7.1 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (ES+) 525.3, (ES−)501.2 (M−1).

Step 5: Preparation of tert-butyl3-(5-((3-(1-phenylpentyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(32e)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32d) (137 mg, 0.273 mmol) in anhydrous methanol (20 mL), cooled to 0°C., were added di-tert-butyl dicarbonate (178 mg, 0.818 mmol),nickel(II) chloride (12.96 mg, 0.055 mmol) and portion wise sodiumborohydride (61.9 mg, 1.636 mmol) over a period of 5 mins. The reactionmixture was stirred for 36 min at room temperature, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.059 mL, 0.545 mmol).

The mixture was allowed to stir for 30 minutes and concentrated invaccum to dryness. To the residue was added water (25 mL) and with ethylacetate (2×25 mL). The organic layer was combined dried, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [(silica gel 12 g, eluting with ethylacetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(3-(1-phenylpentyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(32e) (75 mg, 45.3% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=2.2 Hz, 3H), 7.45-7.38 (m, 2H),7.35 (d, J=7.6 Hz, 2H), 7.31-7.21 (m, 5H), 7.15 (dt, J=8.6, 4.0 Hz, 1H),7.08 (d, J=7.7 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.87 (t, J=7.8 Hz, 1H),1.98 (d, J=8.3 Hz, 2H), 1.36 (s, 9H), 1.28 (d, J=7.2 Hz, 2H), 1.22-1.10(m, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (ES+) 629.3 (M+Na), (ES−) 605.2(M−1), 641.3 (M+Cl).

Step 6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32f)

To a stirred solution of tert-butyl3-(5-(3-(1-phenylpentyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(32e)(0.065 g, 0.107 mmol) in methanol (5 mL) was added 4 M HCl indioxane (0.357 mL, 4.29 mmol) and heated to reflux for 30 minutes.

The reaction was cooled to room temperature and concentrated in vacuumto dryness. To the residue was added methanol (50 mL) and concentratedin vacuum to dryness. The residue was triturated with ether (25 mL) andthe solid separated was collected by filtration, dried in vacuum toafford1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(32f) (60 mg) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H, D₂O exchangeable), 8.31 (s, 3H, D₂O exchangeable), 7.71 (d,J=1.9 Hz, 1H), 7.66 (s, 1H), 7.62-7.57 (m, 1H), 7.56-7.48 (m, 4H),7.32-7.20 (m, 5H), 7.20-7.13 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.13 (s,2H), 3.87 (t, J=7.8 Hz, 1H), 1.98 (d, J=7.5 Hz, 2H), 1.29 (p, J=7.3 Hz,2H), 1.16 (d, J=7.7 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (ES+) 507.3(M+1), 508.3 (M+2), (ES−) 505.2 (M−1), 541.2 (M+35).

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(33e) and1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(33f) Step-1: Preparation of (4-chloro-3-nitrophenyl)(phenyl)methanol(33b)

To a solution of 4-chloro-3-nitrobenzaldehyde (33a) (1 g, 5.39 mmol) intetrahydrofuran (20 mL) cooled to 0° C. was added phenylmagnesiumbromide (8.08 mL, 8.08 mmol, 1 M solution in THF) dropwise over a periodof 2 mins. The reaction mixture was allowed to warm to room temperaturefor 14 h, quenched with saturated ammonium chloride (50 mL) andextracted with ethyl acetate (100 mL, 50 mL). The combined extracts werewashed with brine (50 mL), dried over MgSO₄, filtered and concentratedin vacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with hexanes/ethyl acetate0-100%) to afford pure (4-chloro-3-nitrophenyl)(phenyl)methanol (33b)(653 mg, 46.0% yield) as a yellow semisolid; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.67 (dd, J=8.4, 1.9 Hz,1H), 7.45-7.38 (m, 2H), 7.38-7.29 (m, 2H), 7.28-7.21 (m, 1H), 6.31 (d,J=4.0 Hz, 1H), 5.84 (d, J=4.0 Hz, 1H); MS (ES+) 286.1 (M+23), 262.1(M−1), 308.1 (M+35).

Step-2: Preparation of (3-amino-4-chlorophenyl)(phenyl)methanol (33c)

To a stirred solution of (4-chloro-3-nitrophenyl)(phenyl)methanol (33b)(600 mg, 2.276 mmol) in acetic Acid (10 mL) was added iron powder (762mg, 13.65 mmol) and heated at 60° C. for 3 h. The reaction mixture wasdiluted with ethanol (100 mL) and filtered through celite. The filtratewas concentrated in vacuum and purified by flash column chromatography(silica gel, 12 g, eluting with 0-1005 CMA 80 in chloroform) to afford(3-amino-4-chlorophenyl)(phenyl)methanol (33c) (383 mg, 1.639 mmol,72.0% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37-7.25 (m, 4H),7.23-7.16 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.53(dd, J=8.3, 2.1 Hz, 1H), 5.82 (s, 1H, D₂O exchangeable), 5.53 (s, 1H),5.29 (s, 2H, D₂O exchangeable); MS (ES+) 234.1 (M+1), 236.1 (M+3).

Step-3: Preparation of tert-butyl3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(33d)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.193 g, 0.5 mmol) in N,N-dimethylformamide (3.02 mL, 39.0mmol) was added 3(3-amino-4-chlorophenyl)(phenyl)methanol (33c) (0.140g, 0.6 mmol), N-ethyl-N-isopropylpropan-2-amine (0.697 mL, 4.0 mmol),Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP) (0.256 g,0.55 mmol) and at room temperature for 16 h. The reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (100 mL and50 mL). The organic layers were combined dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to dryness. Theresidue was purified by flash column chromatography (silica gel 12 g,eluting with hexanes in ethyl acetate/hexanes from 0-100%) to affordtert-butyl3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(33d) (0.059 g, 19.63% yield) as an oil. MS (ES−) 599.2, 601.2 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(33e) and1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(33f)

To a stirred solution of tert-butyl3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(33d) (0.053 g, 0.088 mmol) in ethanol (5 mL) was added conc. HCl (0.294mL, 3.53 mmol) and stirred overnight at room temperature overnight. Thereaction was heated at reflux for 2 h and concentrated in vacuum toremove excess hydrochloric acid. The residue was dissolved in ethanoland adsorbed on silica gel. The silica gel slurry was purified by flashcolumn chromatography (eluting with methanol in chloroform 0 to 20%) toafford:

-   -   1.        1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (33e) (7 mg, 15.01%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)        δ 10.52 (s, 1H, D₂O exchangeable), 7.53 (t, J=8.9 Hz, 4H),        7.49-7.40 (m, 3H), 7.34 (t, J=4.5 Hz, 6H), 7.30-7.23 (m, 2H),        5.47 (s, 1H), 3.78 (s, 2H), 3.42 (q, J=7.1 Hz, 2H), 1.16 (t,        J=7.0 Hz, 3H); MS (ES+) 529.2 (M), 531.2 (M+2); (ES−) 529.1 (M),        527.1 (M−2).    -   2.        1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (33f) (8 mg, 18.11% yield) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.19 (d, J=190.4 Hz, 1H, D₂O exchangeable), 7.55 (d,        J=7.6 Hz, 3H), 7.49-7.40 (m, 3H), 7.39-7.16 (m, 9H), 6.08 (d,        J=4.2 Hz, 1H, D₂O exchangeable), 5.70 (s, 1H), 3.80 (s, 2H); MS        (ES+) 501.1 (M), 503.1 (M+2); (ES−) 499.1 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c) and1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34d) Step 1: Preparation of (3-Amino-4-fluorophenyl)(phenyl)methanol(26c)

To a stirred solution of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b)(1.077 g, 4.36 10 mmol) in anhydrous methanol (20 mL), cooled to 0° C.,was added nickel(II) chloride hexahydrate (0.259 g, 1.089 mmol) followedby sodium borohydride (0.989 g, 26.1 mmol) portionwise over a 30 minsperiod. The reaction mixture was stirred for 15 min at room temperature.The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.941 mL, 8.71 mmol) stirred for 30minutes and concentrated in vacuum to dryness. The residue was dissolvedin ethyl acetate (25 mL), washed with water (25 mL), brine (25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 12 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish(3-Amino-4-fluorophenyl)(phenyl)methanol (26c) (0.813 g, 86% yield) asan oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.36-7.25 (m, 4H), 7.22-7.14 (m,1H), 6.87 (dd, J=11.5, 8.2 Hz, 1H), 6.76 (dd, J=8.9, 2.2 Hz, 1H), 6.50(ddd, J=8.2, 4.5, 2.2 Hz, 1H), 5.76 (d, J=3.9 Hz, 1H), 5.52 (d, J=3.9Hz, 1H), 5.06 (s, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −137.80-−137.95 (m);MS (ES+) 218 (M+1); (ES−) 216 (M−1).

Step 2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34a)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1 g, 3.56 mmol) in N,N-dimethylformamide (21.48 mL) was added(3-amino-4-fluorophenyl)(phenyl)methanol (26c) (0.773 g, 3.56 mmol),bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop) (1.658 g,3.56 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.10 mL, 17.78 mmol)successively under a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 h andquenched with water (100 mL). The reaction was extracted with ethylacetate (2×100 mL) and the combined organic layers were washed withbrine (50 mL), dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography [silicagel 40 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish(34a) (0.763 g, 45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H, D₂O exchangeable), 8.12 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.94-7.86 (m, 1H), 7.76-7.68 (m, 2H), 7.52 (dd,J=7.6, 2.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.35-7.31 (m, 2H), 7.30 (d,J=1.0 Hz, 1H), 7.27 (q, J=1.9 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.24-7.17(m, 1H), 6.01 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.69 (d, J=4.0 Hz,1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.99, −123.32; MS (ES⁺): MS (ES+)503.1 (M+Na), (ES−) 479.1 (M−1), 959.3 (2M−1).

Step 3: Preparation of tert-butyl3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34b)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34a) (0.730 g, 1.520 mmol) in anhydrous methanol (15 mL), cooled to 0°C. were added di-tert-butyl dicarbonate [(Boc)₂O)] (0.995 g, 4.56 mmol),nickel(II) chloride hexahydrate (0.072 g, 0.304 mmol) and sodiumborohydride (0.345 g, 9.12 mmol) in small portions over 5 mins. Thereaction mixture was stirred for 20 min at room temperature, quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.328 mL, 3.04 mmol) andstirred for 30 mins. The reaction mixture was concentrated in vacuum andthe residue was treated with water (50 mL) and extracted with ethylacetate (2×25 mL). Organic layers were combined, dried over MgSO₄ andexcess solvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography [(silica gel 25 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34b) (0.458 g, 52% yield) as a greasy solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.56 (s, 1H, D₂O exchangeable), 7.57 (m, 2H), 7.51 (t, J=6.2 Hz, 1H),7.46-7.39 (m, 2H), 7.38-7.31 (m, 4H), 7.30 (d, J=0.9 Hz, 1H), 7.29-7.17(m, 3H), 6.00 (d, J=4.0 Hz, 1H, D₂O exchangeable), 5.69 (d, J=3.9 Hz,1H), 4.19 (d, J=6.2 Hz, 2H), 1.38 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.82, −123.71; MS (ES+) 607.2 (M+Na), (ES−) 583.2 (M−1).

Step 4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c) and1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34d)

To a solution of tert-butyl3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34b) (0.277 g, 0.474 mmol) in 1,4-dioxane (10 mL) was added at roomtemperature dropwise hydrogen chloride (4 M in 1,4-dioxane, 6.87 mL,27.5 mmol) and stirred at room temperature for 14 h. The reactionmixture was diluted with 75 mL of hexanes and the resulting greasy solidwas collected by filtration. The residue (greasy solid) was re-dissolvedin chloroform (40 mL)/cyclopropylmethanol (1.880 mL, 22.75 mmol) added 3g of silica gel and stirred at room temperature for 30 min. The mixturewas concentrated in vacuum to dryness and the slurry obtained waspurified by flash column chromatography [(silica gel 25 g, eluting withCMA80 in chloroform from 0-100%)] to afford:

-   -   1.        1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (34d) (19 mg, 8% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 10.55 (s,        1H), 7.58 (d, J=4.2 Hz, 2H), 7.52 (s, 1H), 7.47-7.40 (m, 2H),        7.38-7.17 (m, 8H), 6.01 (d, J=4.0 Hz, 1H), 5.68 (d, J=2.1 Hz,        1H), 3.78 (s, 2H); ¹HNMR (300 MHz, DMSO-d₆ D₂O) δ 7.62-7.54 (m,        2H), 7.53-7.42 (m, 3H), 7.38-7.18 (m, 8H), 5.68 (s, 1H), 3.77        (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −123.78; MS (ES⁺):        MS (ES+) 485.2 (M+1), 969.4 (2M+1), (ES−) 483.2 (M−1), 519.2        (M+Cl), 967.3 (2M−1).    -   2. Second column purification of impure fractions [(silica gel        12 g, eluting with methanol in chloroform from 0 to 100%)]        afforded        1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (34c) (39 mg, 15% yield) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.59 (s, 1H), 7.58 (d, J=5.1 Hz, 2H), 7.52 (d, J=2.0        Hz, 1H), 7.47-7.38 (m, 2H), 7.33 (d, J=4.4 Hz, 5H), 7.28-7.20        (m, 3H), 5.47 (s, 1H), 3.77 (s, 2H), 3.22 (d, J=6.7 Hz, 2H),        1.05 (m, 1H), 0.54-0.38 (m, 2H), 0.21-0.09 (m, 2H); ¹⁹F NMR (282        MHz, DMSO-d₆) δ −60.75, −122.96; MS (ES⁺): MS (ES+) 539.3 (M+1),        (ES−) 537.2 (M−1); Analysis calculated for C₂₉H₂₆F₄N₄O₂: C,        64.68; H, 4.87; N, 10.40; found: C, 64.58; H, 5.07; N, 10.19.

Alternative Method for Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c) Step-1: Preparation of1-(3-Cyanophenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34e)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34a) (1.1 g, 2.290 mmol) in cyclopropylmethanol (14.80 mL, 206 mmol)was added Ytterbium(III) trifluoromethanesulfonate (1.065 g, 1.717 mmol)and heated with stirring at 80° C. for 16 h. Excess solvent waspumped-off, and residue was dried under reduced pressure. The residueobtained was purified by flash column chromatography [silica gel 40 g,eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34e) (1.014 g, 83% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.57 (s, 1H, D₂O exchangeable), 8.18-8.09 (m, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.79-7.67 (m, 2H), 7.59-7.48 (m,1H), 7.38-7.31 (m, 4H), 7.29-7.20 (m, 3H), 5.48 (s, 1H), 3.22 (d, J=6.7Hz, 2H), 1.04 (dddd, J=12.2, 8.1, 4.0, 2.6 Hz, 1H), 0.53-0.39 (m, 2H),0.14 (tq, J=4.6, 2.1 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.99,−122.52; MS (ES⁺): MS (ES+) 557.2 (M+Na), MS (ES−) 533.1 (M−1); IR (KBr,cm⁻¹): 2235 cm⁻¹ (C—N stretching).

Step-2: Preparation of tert-butyl3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34f)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34e) (0.996 g, 1.863 mmol) in anhydrous methanol (10 mL) cooled to 0°C., were added di-tert-butyl dicarbonate [(Boc)₂O)](1.220 g, 5.59 mmol),sodium borohydride (0.423 g, 11.18 mmol) in small portions over a periodof 5 min. The reaction was exothermic and effervescent. The reactionmixture was stirred for 15 min and concentrated in vacuum. The residuewas treated with water (15 mL), and extracted with ethyl acetate (2×25mL). Organic layers were combined dried over anhydrous MgSO₄, filtered,and excess solvents were pumped-off under reduced pressure. The residuewas purified by flash column chromatography [(silica gel 25 g, elutingwith ethyl acetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34f) (445 mg, 37% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H, D₂O exchangeable), 7.58 (d, J=5.9 Hz, 2H), 7.51 (t, J=6.2Hz, 1H), 7.45-7.30 (m, 7H), 7.29-7.21 (m, 3H), 5.47 (s, 1H), 4.19 (d,J=6.3 Hz, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.38 (s, 9H), 1.10-0.99 (m, 1H),0.51-0.41 (m, 2H), 0.19-0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.83, −122.90; MS (ES⁺): MS (ES+) 661.29 (M+Na), MS (ES−) 637.2 (M−1).

Step-3: Preparation of1-(3-(Aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c)

To a solution of tert-butyl3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(34f) (0.431 g, 0.675 mmol) in 1,4-Dioxane (20 mL) was added a solutionof 4M hydrogen chloride in 1,4-dioxane (9.79 mL, 39.1 mmol) and stirredat room temperature for 14 h. The reaction mixture was evaporated todryness and the residue obtained was purified by flash columnchromatography [(silica gel 40 g, eluting with methanol in chloroformfrom 0-100%)] to furnish1-(3-(Aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c) (0.209 g, 0.388 mmol, 57.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.59 (s, 1H, D₂O exchangeable), 7.58 (d, J=5.1 Hz, 2H),7.52 (d, J=2.0 Hz, 1H), 7.47-7.38 (m, 2H), 7.33 (d, J=4.4 Hz, 5H),7.28-7.20 (m, 3H), 5.47 (s, 1H), 3.77 (s, 2H), 3.22 (d, J=6.7 Hz, 2H),1.05 (m, 1H), 0.54-0.38 (m, 2H), 0.21-0.09 (m, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −60.75, −122.96; MS (ES+) 539.3 (M+1), (ES−) 537.2 (M−1).Analysis calculated for C₂₉H₂₆F₄N₄O₂: C, 64.68; H, 4.87; N, 10.40;Found: C, 64.58; H, 5.07; N, 10.19.

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(35g) Step-1: Preparation of2-fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b)

To a solution of 2-fluoro-3-nitrobenzoic acid (35a) (5.0 g, 27.0 mmol)in toluene (20.0 mL) was added thionyl chloride (19.71 mL, 270 mmol),one drop of DMF and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness, co-distilled with toluene (10 mL)once and dried under vacuum to remove traces of thionyl chloride. Theacid chloride obtained was dissolved in dichloromethane (40 mL) and toit was added at room temperature N,O-dimethylhydroxylamine hydrochloride(3.95 g, 40.5 mmol) and triethylamine (18.82 mL, 135 mmol). The reactionmixture was stirred at room temperature overnight, washed with water (25mL), brine (25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting with 0-100%, ethyl acetate in hexane) to furnish2-Fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b) (5.062 g, 82% yield)as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (ddd, J=8.3, 7.4,1.7 Hz, 1H), 7.93 (ddd, J=7.5, 5.6, 1.7 Hz, 1H), 7.54 (ddd, J=8.5, 7.7,1.0 Hz, 1H), 3.50 (s, 3H), 3.32 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.00 (t, J=6.6 Hz); MS (ES+) 251.1 (M+Na).

Step-2: Preparation of methyl3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35c)

To a solution of 2-fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b)(3.792 g, 16.62 mmol) in methanol (30 mL) was added Palladium on carbon(0.8 g) and the mixture was hydrogenated at 50 psi for 4 h. The reactionmixture was filtered through Celite and the filtrate was concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting with 0-100% ethyl acetate in hexane) tofurnish methyl 3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35c) (3.072g, 15.50 mmol, 93% yield) as a light brown solid; ¹H NMR (300 MHz,DMSO-d₆) δ 6.90 (t, J=7.7 Hz, 1H), 6.80 (td, J=8.3, 1.8 Hz, 1H), 6.49(ddd, J=7.5, 5.7, 1.8 Hz, 1H), 5.30 (s, 2H), 3.62-3.43 (m, 3H), 3.22 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −138.16; MS (ES+) 221.1 (M+Na).

Step-3: Preparation of (3-amino-2-fluorophenyl)(phenyl)methanone (35d)

A solution of 3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35c) (2.8 g,14.13 mmol) in THF (60 mL) was cooled to 0° C. and treated with phenylmagnesium bromide (28.7 mL, 28.7 mmol) slowly followed by warming up toroom temperature and stirring at room temperature for 14 h. Reaction wasquenched with sat. ammonium chloride (120 mL) and extracted with ethylacetate (2×100 mL). The combined extracts were dried over MgSO₄,filtered, evaporated under reduced pressure. The residue was purified byflash column chromatography [(silica gel 80 g, eluting with ethylacetate in hexanes from 0 to 50%)] to furnish(3-amino-2-fluorophenyl)(phenyl)methanone (35d) (1.297 g, 43% yield) asa pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.80-7.73 (m, 2H),7.73-7.66 (m, 1H), 7.62-7.52 (m, 2H), 7.08-6.92 (m, 2H), 6.67-6.55 (m,1H), 5.44 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −135.94; MS (ES⁺): MS(ES+) 238.1 (M+Na), MS (ES−) 214.0 (M−1).

Step-4: Preparation ofN-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(35e)

In a 100 mL single-necked flask containing a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.38 g, 4.91 mmol), (3-amino-2-fluorophenyl)(phenyl)methanone (35d)(1.056 g, 4.91 mmol) in N,N-dimethylformamide (30 mL) was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop) (2.288 g,4.91 mmol), N-ethyl-N-isopropylpropan-2-amine (4.27 mL, 24.54 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder nitrogen atmosphere. The reaction was quenched with water (100 mL)and extracted with ethyl acetate (2×100 mL). The organic layers werecombined washed with brine (50 mL), dried over anhydrous MgSO₄,filtered, and evaporated to dryness. The residue was purified by flashcolumn chromatography twice [silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%] to furnishN-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(35e) (0.287 g, 12% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.73 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.85 (td, J=7.4,2.1 Hz, 1H), 7.78 (d, J=2.6 Hz, 2H), 7.76 (d, J=1.9 Hz, 2H), 7.73 (s,1H), 7.58 (dd, J=8.3, 7.0 Hz, 2H), 7.48-7.35 (m, 2H); ¹H NMR (300 MHz,DMSO-d₆ D₂O) δ 8.13 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H),7.91 (ddd, J=8.1, 2.3, 1.2 Hz, 1H), 7.84 (td, J=7.3, 2.5 Hz, 1H),7.80-7.70 (m, 5H), 7.59 (t, J=7.7 Hz, 2H), 7.48-7.36 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −61.00, −122.24; IR (KBr, cm⁻¹): 2233 cm⁻¹ (C—Nstretching); MS (ES⁺): MS (ES+) 479.1 (M+1), 501.1 (M+Na), (ES−) 477.1(M−1), 955.2 (M+Cl).

Step-5: Preparation of tert-butyl3-(5-(2-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(35f)

To a stirred solution ofN-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(35e) (0.276 g, 0.577 mmol) in anhydrous methanol (20 mL) cooled to 0°C., were added, di-tert-butyl dicarbonate [(Boc)₂O)] (0.378 g, 1.731mmol), nickel(II) chloride hexahydrate (0.027 g, 0.115 mmol), sodiumborohydride (0.131 g, 3.46 mmol) was then added in small portions over aperiod of 5 min. The reaction mixture was stirred for 50 min at 0° C.,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.125 mL, 1.154mmol), stirred for 30 minutes and concentrated in vacuum to dryness. Theresidue was treated with water (25 mL) and extracted with ethyl acetate(2×25 mL). Combined organic layers were dried over MgSO₄, filtered, andexcess solvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography [(silica gel 25 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(2-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(35f) (0.212 g, 63% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.54 (s, 1H, D₂O exchangeable), 7.58 (s, 1H), 7.54-7.46 (m, 3H),7.46-7.38 (m, 2H), 7.38-7.30 (m, 5H), 7.26-7.15 (m, 2H), 6.08 (d, J=4.3Hz, 1H, D₂O exchangeable), 5.93 (d, J=4.2 Hz, 1H), 4.18 (d, J=6.2 Hz,2H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.83, −127.57; MS(ES⁺): MS (ES+) 607.2 (M+Na), (ES−) 583.2 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(35g)

To a solution of tert-butyl3-(5-(2-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(35f) (0.151 g, 0.258 mmol) in 1,4-dioxane (18 mL) was added dropwisehydrogen chloride (2.78 mL, 11.11 mmol, 4 M in 1,4-dioxane) and stirredat room temperature for 14 h. Excess solvent was pumped-off underreduced pressure. The residue was dissolved inchloroform/cyclopropylmethanol (1.452 mL, 17.57 mmol) and slurried with2 g of silica gel, then the residue was purified by flash columnchromatography [(silica gel 25 g, eluting with methanol in chloroformfrom 0 to 100%)] to furnish BCX-6967 (0.109 g, 87% yield) as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H, D₂O exchangeable), 7.64(s, 2H), 7.55-7.43 (m, 5H), 7.32 (d, J=6.5 Hz, 4H), 7.26-7.14 (m, 2H),6.10 (d, J=4.2 Hz, 1H, D₂O exchangeable), 5.92 (d, J=3.9 Hz, 1H), 4.00(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −127.34; MS (ES⁺): MS(ES+) 485.2 (M+1), (ES−) 483.2 (M−1), 519.1 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36d) Step-1: Preparation of (3-amino-2-fluorophenyl)(phenyl)methanol(36a)

To a stirred solution of (3-amino-2-fluorophenyl)(phenyl)methanone (35d)(1.25 g, 5.81 mmol) in anhydrous methanol (50 mL) cooled to 0° C. wasadded nickel(II) chloride (0.345 g, 1.452 mmol) and sodium borohydride(0.879 g, 23.23 mmol) in small portions over a period of 5 min. Thereaction mixture was stirred for 15 min, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.255 mL, 11.62 mmol) stirred foradditional 30 mins and concentrated in vacuum to dryness. The residueobtained was treated with water (50 mL), and extracted with ethylacetate (2×75 mL). Organic layers were combined, dried over MgSO₄,filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography [(silica gel 40 g, eluting withethyl acetate in hexanes from 0 to 50%)] to furnish(3-amino-2-fluorophenyl)(phenyl)methanol (36a) (0.834 g, 66% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37-7.24 (m, 4H), 7.23-7.16(m, 1H), 6.88-6.78 (m, 1H), 6.64 (dddd, J=18.3, 9.3, 7.1, 1.8 Hz, 2H),5.94-5.74 (m, 2H), 5.03 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −140.94; MS (ES⁺): MS (ES+) 240.1 (M+Na), MS (ES−) 216.1(M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36b)

In a 250 mL single-necked flask containing a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.263 g, 4.49 mmol), (3-amino-2-fluorophenyl)(phenyl)methanol (36a)(0.813 g, 3.74 mmol) in N,N-dimethylformamide (DMF) (22.60 mL, 292 mmol)was added bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop,2.094 g, 4.49 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (3.26mL, 18.71 mmol) successively in a positive flow of nitrogen at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 16 h, diluted with water (100 mL) and extracted withethyl acetate (2×100 mL). The organic layers were combined, washed withbrine (50 mL), dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue obtained was purified by flash columnchromatography twice [silica gel 40 g, eluting with ethyl acetate inhexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36b) (1.378 g, 77% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.50 (s, 1H), 8.17-8.10 (m, 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.89(ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.77-7.68 (m, 2H), 7.46 (t, J=7.1 Hz,2H), 7.39-7.27 (m, 4H), 7.26-7.15 (m, 2H), 6.09 (d, J=4.3 Hz, 1H, D₂Oexchangeable), 5.93 (d, J=3.7 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−61.00, −127.24; MS (ES⁺): MS (ES+) 503.1 (M+Na), MS (ES−) 479.1 (M−1);IR (KBr, cm⁻¹): 2235 cm⁻¹ (C—N stretching).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36c)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36b) (0.193 g, 0.402 mmol) in cyclopropylmethanol (2.89 mL, 40.2 mmol)was added Ytterbium(III) trifluoromethanesulfonate (0.498 g, 0.803 mmol)and heated at 80° C. for 16 h. Excess solvent was pumped-off, dilutedwith chloroform (2×50 mL), and filtered through a Celite pad. Thefiltrate was concentrated in vacuum and the residue obtained waspurified by flash column chromatography [silica gel 25 g, eluting withethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36c) (63 mg, 29% yield) as a pale yellow solid; ¹HNMR (300 MHz,DMSO-d₆) δ 10.52 (s, 1H), 8.17-8.08 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz,1H), 7.94-7.87 (m, 1H), 7.78-7.68 (m, 2H), 7.49 (t, J=7.5 Hz, 1H),7.42-7.31 (m, 5H), 7.29-7.17 (m, 2H), 5.72 (s, 1H), 3.27 (d, J=6.8 Hz,2H), 1.09-1.02 (m, 1H), 0.52-0.42 (m, 2H), 0.20-0.11 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.99, −126.92; MS (ES⁺): MS (ES+) 557.16 (M+Na),(ES−) 533.22 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36d)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36c) (0.060 g, 0.112 mmol) in anhydrous methanol (10 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.027 g, 0.112 mmol) andsodium borohydride (0.025 g, 0.674 mmol) in small portions over 5 min.The reaction mixture was stirred for 15 min and concentrated in vacuumto dryness. The residue obtained was purified by flash columnchromatography [(silica gel 2×12 g, eluting with methanol/chloroformfrom 0 to 100%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36d) (24 mg, 40% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.58 (s, 1H), 7.55-7.49 (m, 2H), 7.46-7.40 (m, 2H), 7.40-7.30 (m, 6H),7.30-7.18 (m, 2H), 5.72 (s, 1H), 3.78 (s, 2H), 3.27 (d, J=6.8 Hz, 2H),1.12-0.98 (m, 1H), 0.54-0.41 (m, 2H), 0.15 (ddd, J=5.5, 4.7, 3.6 Hz,2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 7.54 (s, 1H), 7.51-7.44 (m, 4H),7.43-7.39 (m, 1H), 7.36 (d, J=4.5 Hz, 5H), 7.31-7.21 (m, 2H), 5.72 (s,1H), 3.76 (s, 2H), 3.27 (d, J=6.8 Hz, 2H), 1.13-0.98 (m, 1H), 0.56-0.40(m, 2H), 0.15 (dt, J=4.4, 2.8 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.76, −127.15; MS (ES⁺): MS (ES+) 539.2 (M+1), MS (ES−) 537.2 (M−1),573.1 (M+Cl).

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(37a) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(37b)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34c) (1.24 gms) was purified by chiral preparation HPLC using ChiralAD-H column 80/20/0.1 (Hexane/ethanol/TEA) 0.8 mL/min UV 260 nM, 20 minsrun time (Temp 20° C.) to obtain:

-   -   1.        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (37a) (213 mgs, ee=18.32%) Rt=14.453 [40.8415%, (−)-isomer];        Rt=15.713 [59.1585% (+)-isomer]. This material was repurified by        flash column chromatography (silica gel 2×12g, eluting with        0-100% ethyl cetate/methanol (9:1) in hexanes) to furnish (45        mg) pure product; ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O        exchangeable), 7.58 (d, J=7.0 Hz, 2H), 7.51 (s, 1H), 7.47-7.40        (m, 2H), 7.33 (d, J=4.3 Hz, 5H), 7.25 (dd, J=8.3, 3.8 Hz, 3H),        5.47 (s, 1H), 3.77 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.03 (dd,        J=11.7, 5.5 Hz, 1H), 0.56-0.39 (m, 2H), 0.22-0.06 (m, 2H); ¹⁹F        NMR (282 MHz, DMSO-d₆) δ −60.73, −122.98; MS (ES+) 539.2 (M+1),        537.2 (M−1), 573.1 (M+Cl).    -   2.        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (37b) (55 mg, ee=37.8%) Rt=14.433 [68.9002%, (−)-isomer]        Rt=15.793 [31.0998%, (+)-isomer]. This material was repurified        by flash column chromatography (silica gel 4 g, eluting with        chloroform/methanol (1:0 to 9:1) to furnish (12.3 mg) pure        product, [α]_(D)=−3.90 [CH₃OH, 0.615].

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38d) Step-1: Preparation ofN-(5-(chloro(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38a)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(34a) (0.462 g, 0.962 mmol) in dichloromethane (10 mL) at 0° C. wasadded thionyl chloride (0.211 mL, 2.89 mmol) and allowed to warm to roomtemperature over 3 h. To the reaction mixture was concentrated in vacuumto dryness. The residue was purified by flash column chromatography(silica gel 25 g, eluting with ethyl acetate in hexanes from 0-100%) toaffordN-(5-(chloro(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38a) (0.208 g, 0.417 mmol, 43.4% yield) as a pale yellow greasy solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (t, J=1.6 Hz, 1H), 8.02 (d, J=1.8 Hz,2H), 7.88 (dd, J=7.2, 2.3 Hz, 1H), 7.83-7.78 (m, 3H), 7.77-7.73 (m, 1H),7.64 (ddd, J=8.9, 4.9, 2.3 Hz, 1H), 7.48 (dd, J=10.0, 8.7 Hz, 1H), 7.32(dt, J=4.3, 1.1 Hz, 4H), 6.57 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−61.09, −121.678; MS (ES+) 534.2 (M+1); (ES−) 533.2 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38b)

To a solution ofN-(5-(chloro(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38a) (0.17 g, 0.341 mmol) in THF (10 mL) was addedcyclopropylmethanamine (0.591 mL, 6.82 mmol) and heat at refluxovernight. An additional amount of cyclopropylmethanamine (0.591 mL,6.82 mmol) and heated at reflux for 48h. The reaction mixture wasquenched with water (10 mL) and extracted with ethyl acetate (2×10 mL).The combined organic layer was washed with brine (10 mL), dried,filtered and concentrated in vacuum. The residue was purified by flashcolumn chromatography (silica gel 12 g, eluting 0-100% ethyl acetate inhexane) to afford1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38b) (0.12 g, 0.225 mmol, 66.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.15-8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.94-7.86 (m, 1H), 7.77-7.69 (m, 2H), 7.57 (d, J=7.0 Hz, 1H),7.42-7.37 (m, 2H), 7.36-7.15 (m, 6H), 4.84 (s, 1H), 2.26 (d, J=6.3 Hz,2H), 0.98-0.83 (m, 1H), 0.43-0.31 (m, 2H), 0.04 (dd, J=5.3, 3.9 Hz, 2H);19F NMR (282 MHz, DMSO-d₆) δ −61.06, −123.36; MS (ES+) 534.2 (M+1);(ES−) 533.2 (M−1).

Step-3: Preparation of tert-Butyl3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(38c)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38b) (0.12 g, 0.225 mmol) in anhydrous methanol (10 mL), cooled to 0°C., was added di-tert-butyl dicarbonate [(Boc)₂O)] (0.196 g, 0.900mmol), nickel(II) chloride hexahydrate (0.013 g, 0.056 mmol). Sodiumborohydride (0.051 g, 1.350 mmol) was added to the reaction mixture insmall portions over 15 min. The reaction mixture was stirred for 15 min,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.126 mL, 1.163 mmol)and stirred for 30 minutes before solvent was evaporated under vacuum.The residue was treated with water (15 mL), and extrated with ethylacetate (2×25 mL). The organic layers were combined dried over MgSO₄filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography [(silica gel 12 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish tert-butyl3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(38c) (0.12 g, 0.188 mmol, 32.4% yield) as a colorless oil; ¹H NMR (300MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.58 (s, 1H),7.50 (dd, J=12.6, 6.1 Hz, 1H), 7.45-7.25 (m, 10H), 7.22-7.15 (m, 2H),4.84 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.26 (d, J=6.5 Hz, 2H), 1.39 (s,9H), 0.92 (dd, J=13.7, 5.7 Hz, 1H), 0.43-0.31 (m, 2H), 0.04 (td, J=5.6,4.9, 2.1 Hz, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.82, −123.76; MS (ES+)638.3 (M+1); (ES−) 636.3 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38d)

To a solution of tert-butyl3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(38c) (0.12 g, 0.188 mmol) in methanol (5 mL) was added HCl (0.286 mL,9.41 mmol) and stirred at reflux for 2 h. The reaction mixture wasconcentrated in vacuum to dryness. Trace amounts of HCl and water wasremoved by azeotropic distillation under vacuum using ethanol (10 mL)and Toluene (10 mL). The residue was dried in a vacuum pump and purifiedby flash column chromatography (silica gel 8 g, eluting with 0-25%methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38d) (0.044 g, 0.082 mmol, 43.5% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.71 (s, 1H), 7.70-7.58 (m, 2H),7.60-7.48 (m, 3H), 7.47-7.33 (m, 3H), 7.34-7.25 (m, 3H), 7.20 (dd,J=8.4, 5.7 Hz, 2H), 4.94 (s, 1H), 4.12 (s, 2H), 2.32 (d, J=6.7 Hz, 2H),1.01-0.86 (m, 1H), 0.45-0.34 (m, 2H), 0.13-0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.83; −123.36; MS (ES+) 538.3 (M+1); (ES−) 536.1(M−1), 572.2 (M+Cl); Analysis calculated for C₂₉H₂₇F₄N₅O1.25HCl.H₂O: C,57.94; H, 5.07; Cl, 7.37; N, 11.65; Found: C, 58.12; H, 4.99; Cl, 7.40;N, 11.34.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(39e) Step-1: Preparation of(E/Z)-3-(3-aminophenyl)-3-phenylacrylonitrile (39b)

To a suspension of NaH (0.507 g, 12.68 mmol) in DME (10 mL) was addeddiethyl cyanomethylphosphonate (39a) (1.835 mL, 11.66 mmol) at 0° C. Thereaction was warmed to room temperature and stirred for 1 hr. To thereaction mixture was added a solution of(3-aminophenyl)(phenyl)methanone (18a) (1 g, 5.07 mmol) in DME (10.00mL) at 0° C. and stirred at room temperature overnight. The reaction wasquenched with saturated aqueous ammonium chloride (50 mL) at 0° C.,extracted with ethyl acetate (2×100 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The residue was purified by flash columnchromatography (silicagel, 40 g) to afford(E/Z)-3-(3-aminophenyl)-3-phenylacrylonitrile (39b) (1.1 g, 98%); MS(ES+) 243.1 (M+Na); (ES−) 219.1 (M−1).

Step-2: Preparation of 3-(3-aminophenyl)-3-phenylpropanenitrile (39c)

To a suspension of Pd/C (10%) (0.012 g, 0.113 mmol) in methanol (30 mL)was added (E/Z)-3-(3-aminophenyl)-3-phenylacrylonitrile (39b) (0.25 g,1.135 mmol) and hydrogenated at 60 psi for 14 h. The reaction mixturewas filtered through a Celite pad and concentrated in vacuum to dryness.The crude residue was purified by flash column chromatography (silicagel, 12 g, eluting with ethyl acetate in hexanes 0 to 100%) to afford3-(3-aminophenyl)-3-phenylpropanenitrile (39c) (180 mg, 71.3%); MS (ES+)245.1 (M+Na); (ES−) 221.1 (M−1).

Step-3: Preparation of tert-butyl3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(39d)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (144 mg, 0.375 mmol) in N,N-dimethylformamide (2.5 mL) wasadded 3-(3-aminophenyl)-3-phenylpropanenitrile (39c) (100 mg, 0.45mmol), N-ethyl-N-isopropylpropan-2-amine (0.522 mL, 3.00 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP, 192 mg,0.412 mmol) at room temperature. The reaction mixture was stirred at 25°C. for 16 h. The reaction mixture was diluted with water (25 mL) andextracted with ethyl acetate (100 mL, 50 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered, concentrated in vacuum.The residue was purified by flash column chromatography (silica gel 12g, eluting with ethyl acetate in hexane 0-100%) to afford tert-butyl3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(39d) (180 mg, 81% yield) as colorless solid; MS (ES+) 612.2 (M+Na);(ES−) 588.8 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(39e)

To a stirred solution of tert-butyl3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(39d) (0.090 g, 0.153 mmol) in acetonitrile (4 mL) was addedhydrochloric acid, 4 N in 1,4-dioxane (0.763 mL, 3.05 mmol), stirred atroom temperature for 3 h and concentrated in vacuum to dryness. Theresidue was suspended in ether (30 mL) and the solid that separated wascollected by filtration, dried under vacuum to afford1-(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(39e) (70 mg, 94% yield); ¹HNMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H,),8.38 (s, 3H, D₂O exchangeable), 7.72 (t, J=1.7 Hz, 1H), 7.66 (s, 1H),7.64-7.47 (m, 5H), 7.33 (d, J=4.1 Hz, 5H), 7.26-7.19 (m, 2H), 4.42 (t,J=8.0 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 3.31 (d, J=8.0 Hz, 2H); MS (ES+)490.3 (M+1), (ES−) 488.2 (M−1), 524.2 (M+35).

Preparation ofN-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(40b) Step-1: Preparation of tert-butyl3-(5-((3-(3-amino-3-oxo-1-phenylpropyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(40a)

To a stirred solution of tert-butyl3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(39d) (0.07 g, 0.119 mmol) in MeOH (4 mL) cooled to 0° C. was added concNH₄OH (0.826 mL, 5.94 mmol), hydrogen peroxide 35% solution (1.559 mL,17.81 mmol) and stirred for 16 h at room temperature. The reactionmixture was concentrated in vacuum and the residue obtained was purifiedby flash column chromatography [silica gel 12 g, eluting with 0-100%(9:1) mixture of ethyl acetate and methanol in hexanes] to affordtert-butyl3-(5-(3-(3-amino-3-oxo-1-phenylpropyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(40a) (47 mg, 65.2% yield); MS (ES+) 630.3 (M+Na); (ES−) 606.3 (M−1).

Step-2: Preparation ofN-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(40b)

To a stirred solution of tert-butyl3-(5-(3-(3-amino-3-oxo-1-phenylpropyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(40a) (0.040 g, 0.066 mmol) in methanol (3 mL) was added conc HCl (0.110mL, 1.317 mmol) and heated at reflux for 30 minutes. The reactionmixture was concentrated in vacuum to dryness.

The residue was suspended in ether and solid separated was collected byfiltration, dried in vacuum. The solid was purified by flash columnchromatography (silica gel 4 g, eluting with methanol in chloroform 0 to20%) to affordN-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(40b) (15 mg, 44.9% yield) as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H, D₂O exchangeable), 7.67 (s, 1H), 7.62 (s, 1H), 7.60-7.43(m, 5H), 7.39 (s, 1H), 7.30-7.21 (m, 5H), 7.17 (d, J=6.7 Hz, 1H), 7.08(d, J=7.3 Hz, 1H), 6.77 (s, 1H), 4.42 (s, 1H), 4.05 (s, 2H), 2.78 (dd,J=7.9, 3.6 Hz, 2H); MS (ES+) 508.3 (M+1), (ES−) 542.2 (M+35).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e)Step-1: Preparation ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41a)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(5.42 g, 19.27 mmol) in DMF (100 mL) was added at room temperature(3-aminophenyl)(phenyl)methanone (18a) (3.8 g, 19.27 mmol)N-ethyl-N-isopropylpropan-2-amine (27 mL, 155 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop) (9.42 g,19.42 mmol). The resulting reaction mixture was stirred at roomtemperature for 39 h under nitrogen atmosphere and diluted with ethylacetate (600 mL). The reaction mixture was washed with water (2×300 mL),brine (200 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel 120 g,eluting with ethyl acetate in hexanes from 0-100%] to affordN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41a) (4.704 g, 53%) as a white solid, contaminated with(3-aminophenyl)(phenyl)methanone; ¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (s,1H), 8.20 (t, J=1.9 Hz, 1H), 8.07-7.98 (m, 3H), 7.93 (ddd, J=8.2, 2.2,1.1 Hz, 1H), 7.78-7.71 (m, 4H), 7.62-7.57 (m, 2H), 7.56 (d, J=3.2 Hz,1H), 7.53 (d, J=2.5 Hz, 1H), 7.50 (dt, J=7.7, 1.5 Hz, 1H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.98.

Step-2: Preparation ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41b)

To a stirred solution ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41a) (4.704 g, 10.22 mmol) in anhydrous methanol (100 mL), cooled to 0°C. were added di-tert-butyl dicarbonate [(Boc)₂O)] (6.76 g, 30.7 mmol),nickel(II) chloride hexahydrate (0.5 g, 2.103 mmol). To the reactionmixture was added sodium borohydride (2.367 g, 61.3 mmol) portionwiseover 45 mins. The reaction mixture was stirred for 15 min at roomtemperature and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (2.3mL, 21.08 mmol). The mixture was stirred for 30 minutes and concentratedin vacuum to dryness. The residue obtained was treated with water (200mL) and extracted with ethyl acetate (400 and 150 mL). Organic layer wascombined dried, filtered and concentrated in vacuum to dryness. Theresidue was purified by flash column chromatography [(silica gel 120 g,eluting with ethyl acetate/hexanes from 0 to 100%)] to furnishN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41b) (2.71 g, 46.8%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.59-7.39 (m, 5H), 7.38-7.17 (m,8H), 7.13 (dt, J=7.6, 1.3 Hz, 1H), 5.94 (d, J=3.8 Hz, 1H), 5.66 (d,J=3.9 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.81; MS (ES+) 589.26 (M+Na)

Step-3: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(41d)

To a solution ofN-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(41b) (0.142 g, 0.25 mmol) in dichloromethane (2.5 mL) at 0° C. wasadded thionyl chloride (0.073 mL, 0.999 mmol) and allowed to warm toroom temperature over 3 h. To the reaction mixture containing tert-butyl3-(5-((3-(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(41c) was added cyclopropylmethanamine (0.217 mL, 2.500 mmol) andstirred at room temperature overnight. TLC analysis shows onlytert-butyl3-(5-((3-(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(41c). To the reaction mixture was added dichloromethane (5 mL) andadditional cyclopropylmethanamine (0.217 mL, 2.5 mmol) and heat atreflux overnight. The reaction mixture was cooled to room temperaturediluted with dichloromethane (10 mL), washed with water (10 mL), dried,filtered and concentrated in vacuum. The residue was purified by flashcolumn chromatography (silica gel 12 g, eluting 0-100% ethyl acetate inhexane) to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(41d) (0.07 g, 0.113 mmol, 45.2% yield) which was good enough to be usedas such for next step; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.65(d, J=2.1 Hz, 1H), 7.58 (s, 1H), 7.56-7.48 (m, 2H), 7.44-7.33 (m, 7H),7.31-7.23 (m, 2H), 7.22-7.16 (m, 2H), 4.81 (s, 1H), 4.19 (d, J=6.2 Hz,2H), 2.24 (d, J=6.6 Hz, 2H), 1.36 (d, J=2.1 Hz, 9H), 0.94 (d, J=10.3 Hz,1H), 0.41-0.34 (m, 2H), 0.09-0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.80; MS (ES+) 620.4 (M+1); (ES−) 618.3 (M−1).

Step-4: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(41d) (0.07 g, 0.113 mmol) in methanol (5 mL) was added conc HCl (0.069mL, 2.259 mmol) and stirred at room temperature overnight followed byheating at reflux for 1 h. The reaction mixture was concentrated invacuum to dryness. Trace amount of HCl and water was removed byazeotropic distillation under vacuum using ethanol (10 mL) and Toluene(10 mL). The residue was dried in a vacuum pump and purified by flashcolumn chromatography (silica gel 8 g, eluting with 0-25% methanol inchloroform) to afford1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e)(0.031 g, 0.060 mmol, 52.8% yield) as a yellow hygroscopic solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.59-7.48(m, 3H), 7.47-7.36 (m, 4H), 7.36-7.23 (m, 4H), 7.23-7.14 (m, 2H), 4.81(s, 1H), 3.79 (s, 2H), 2.38 (d, J=6.7 Hz, 2H), 0.99-0.86 (m, 1H),0.42-0.34 (m, 2H), 0.04 (td, J=5.5, 3.9 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.72; MS (ES+) 520.3 (M+1); (ES−) 518.2 (M−1).

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(42a) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(42b) Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(42a) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(42b)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(38d) (1.09 gms) was purified by preparative SFC Method using thefollowing condition.

Column 3.0 × 25.0 cm ChiralPak AD-H from Chiral Technologies (WestChester, PA) CO₂ Co-solvent (Solvent B) Methanol:Acetonitrile(1:1) with1% Isopropylamine Isocratic Method 30% Co-solvent at 80 mL/min SystemPressure 200 bar Column Temperature 40° C. Sample DiluentMethanol:Acetonitrile (~2:1) Purification afforded;

-   -   1.        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (42b) (463 mg 99.9% ee); ¹H NMR (300 MHz, Methanol-d₄) δ 7.74        (d, J=7.3 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J=4.9 Hz, 2H),        7.43-7.26 (m, 6H), 7.24-7.17 (m, 1H), 7.12 (t, J=9.4 Hz, 1H),        3.85 (s, 2H), 3.21 (s, 1H), 2.37 (d, J=6.9 Hz, 2H), 1.04-0.90        (m, 1H), 0.51-0.42 (m, 2H), 0.11-0.03 (m, 2H); ¹⁹F NMR (282 MHz,        Methanol-d₄) δ −63.73, −127.27; ¹H NMR (300 MHz, DMSO-d₆) δ        10.50 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.56 (s, 1H), 7.51 (s,        1H), 7.47-7.36 (m, 4H), 7.35-7.25 (m, 4H), 7.19 (tt, J=7.3, 2.7        Hz, 2H), 4.83 (s, 1H), 3.77 (s, 2H), 2.26 (d, J=6.6 Hz, 2H),        1.03-0.72 (m, 1H), 0.46-0.25 (m, 2H), 0.12-0.00 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.73, −123.86; MS (ES+) 538.3 (M+1);        (ES−) 536.3 (M−1); Optical Rotation −4.95 (MeOH, 1.415).        -   To a solution of            (−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide            (42b) free base (0.44 mgs, 0.82 mmol) in methanol (4 mL) was            added 2 N methanolic HCl (4 mL, prepared from methanol and            conc HCl, 4 mmol). The mixture was allowed to stay for 15            mins at room temperature concentrated in vacuum to dryness            to furnish            (−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide            (42b) (0.46 gm) as a dihydrochloride; ¹H NMR (300 MHz,            DMSO-d₆) δ 10.84 (s, 1H, 10.30 (d, J=16.0 Hz, 2H), 8.52 (s,            3H), 7.95 (dd, J=7.2, 2.3 Hz, 1H), 7.80-7.69 (m, 5H), 7.64            (dt, J=7.2, 1.7 Hz, 1H), 7.60-7.49 (m, 2H), 7.47-7.33 (m,            4H), 5.74-5.59 (m, 1H), 4.12 (d, J=5.0 Hz, 2H), 2.69 (d,            J=6.6 Hz, 2H), 1.24-1.09 (m, 1H), 0.61-0.50 (m, 2H),            0.36-0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81,            −120.59; MS (ES+) 538.3 (M+1); (ES−) 536.2 (M−1); Analysis            calculated for C₂₉H₂₇F₃N₅O.2HCl.H₂O: C, 55.42; H, 4.97; Cl,            11.28; N, 11.14; Found: C, 55.45; H, 5.13; Cl, 11.12; N,            11.15.    -   2.        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (42a) (461 mg 95.1% ee). contaminated with isopropylamine; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.59 (d, J=7.3 Hz, 1H), 7.51 (s, 1H),        7.45-7.09 (m, 11H), 4.81 (d, J=3.2 Hz, 1H), 3.76 (s, 2H), 2.26        (d, J=6.6 Hz, 2H), 0.92 (d, J=7.7 Hz, 1H), 0.44-0.31 (m, 2H),        0.04 (td, J=5.5, 5.0, 1.9 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.68, −124.17; ¹H NMR (300 MHz, Methanol-d₄) δ 7.65 (d, J=7.3        Hz, 1H), 7.51 (s, 1H), 7.45-7.39 (m, 3H), 7.34 (d, J=7.2 Hz,        2H), 7.29-7.23 (m, 4H), 7.19-7.14 (m, 1H), 7.11-7.02 (m, 1H),        4.84 (s, 1H), 3.81 (s, 2H), 2.33 (d, J=6.9 Hz, 2H), 1.02-0.85        (m, 1H), 0.49-0.38 (m, 2H), 0.09-−0.00 (m, 2H); ¹⁹F NMR (282        MHz, Methanol-d₄) δ −63.71, −127.26; MS (ES+) 538.2 (M+1); (ES−)        536.2 (M−1); Optical Rotation+2.77 (MeOH, 1.95).        -   To a solution of above            (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide            (42a) free base (0.44 mgs, 0.82 mmol) in methanol (4 mL) was            added 2 N methanolic HCl (4 mL, prepared from methanol and            conc HCl, 4 mmol). The mixture was allowed to stay for 15            mins at room temperature concentrated in vacuum to dryness            to furnish            (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide            (42a) (0.46 gm) as a dihydrochloride; ¹H NMR (300 MHz,            DMSO-d₆) δ 10.84 (s, 1H), 10.24 (d, J=20.4 Hz, 2H), 8.52 (s,            3H), 7.95 (dd, J=7.1, 2.3 Hz, 1H), 7.79-7.69 (m, 5H), 7.64            (dt, J=7.2, 1.8 Hz, 1H), 7.59-7.48 (m, 2H), 7.47-7.33 (m,            4H), 5.66 (t, J=6.3 Hz, 1H), 4.12 (q, J=5.7 Hz, 2H), 2.68            (d, J=10.8 Hz, 2H), 2.12 (s, 1H), 1.24-1.12 (m, 1H),            0.63-0.48 (m, 2H), 0.36-0.24 (m, 2H); ¹⁹F NMR (282 MHz,            DMSO-d₆) δ −60.81, −120.62; MS (ES+) 538.3 (M+1); (ES−)            536.2 (M−1); Analysis calculated for            C₂₉H₂₇F₃N₅O.2.25HCl.1.25H₂O.0.5C₃H₉N: C, 54.54; H, 5.44; Cl,            11.88; N, 11.47; Found: C, 54.34; H, 5.64; Cl, 12.12; N,            11.78.            The following analytical SFC Method was used to check purity            of compounds 42a and 42b

Column 4.6 × 100 mm ChiralPak AD-H from Chiral Technologies (WestChester, PA) CO₂ Co-solvent Methanol:Acetonitrile (1:1) with 0.1%(Solvent B) Isopropylamine Isocratic Method 20% Co-solvent at 4 mL/minSystem Pressure 150 bar Column Temperature 40° C. Sample DiluentMethanol Fraction 1 (42b) 1.6 min (Rt) 463 mg 99.9% (ee) 97.1% (Purity)Fraction 2 (42a) 2.9 min (Rt) 461 mg 95.1% (ee) 96.5% (Purity)

Preparation of racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43f);(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43g) and(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43h) Step-1: Preparation of (3-nitrophenyl)(pyridin-2-yl)methanol (43b)

To a solution of 2-bromopyridine (43a) (2.9 mL, 29.8 mmol) in ether (20mL) at −78° C. was added dropwise n-BuLi (19.00 mL, 30.4 mmol) andstirred for 30 mins at −78° C. To the 2-lithiated pyridine was addeddropwise a solution of 3-nitrobenzaldehyde (31a) (4.50 g, 29.8 mmol) inTHF (30 mL) at −78° C. and stirred at −78° C. for 2 h and at roomtemperature for 2 h. The reaction mixture was quenched with saturatedammonium chloride (50 mL). The organic layer was separated and aqueouslayer was extracted with ethyl acetate (75 mL). the organic layers werecombined washed with brine (60 mL), dried, filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel 80 g, eluting with 0-100% ethyl acetate inhexane) to afford (3-nitrophenyl)(pyridin-2-yl)methanol (43b) (1.246 g,18%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (ddd, J=4.8,1.8, 0.9 Hz, 1H), 8.27 (t, J=2.0 Hz, 1H), 8.10 (ddd, J=8.2, 2.4, 1.1 Hz,1H), 7.92-7.76 (m, 2H), 7.68-7.59 (m, 2H), 7.26 (ddd, J=7.5, 4.8, 1.2Hz, 1H), 6.48 (d, J=4.5 Hz, 1H), 5.89 (d, J=4.2 Hz, 1H); MS (ES+): 231.1(M+1).

Step-2: Preparation of (3-aminophenyl)(pyridin-2-yl)methanol (43c)

To a solution of (3-nitrophenyl)(pyridin-2-yl)methanol (43b) (1.152 g,5.00 mmol) in methanol (30 mL) cooled to 0° C. was added nickel(II)chloride hexahydrate (0.297 g, 1.251 mmol) followed by sodiumborohydride (0.773 g, 20.02 mmol) portionwise over a period of 30 min.The reaction mixture was stirred at room temperature for 30 min,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.100 mL, 10.18mmol), stirred for additional 30 min and concentrated in vacuum todryness. The residue was treated with ethyl acetate (150 mL), washedwith water (75 mL). The aqueous phase was extracted again with ethylacetate (75 mL). The combined extracts were washed with brine (75 mL),dried over MgSO₄, filtered and concentrated in vacuum to dryness. Thecrude residue was purified by flash column chromatography [silica geleluting with hexanes/ethyl acetate (1:0 to 0:1)] to afford(3-aminophenyl)(pyridin-2-yl)methanol (43c) (746 mg, 75%) as a lightyellow gum. ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (ddd, J=4.8, 1.8, 0.9 Hz,1H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.50 (dt, J=8.0, 1.1 Hz, 1H), 7.21(ddd, J=7.5, 4.8, 1.2 Hz, 1H), 6.90 (t, J=7.7 Hz, 1H), 6.60 (dd, J=2.3,1.6 Hz, 1H), 6.56-6.50 (m, 1H), 6.37 (ddd, J=7.9, 2.4, 1.1 Hz, 1H), 5.88(d, J=4.0 Hz, 1H), 5.51 (d, J=4.0 Hz, 1H), 5.00 (s, 2H); MS (ES+): 223.1(M+23).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43d)

To a solution of (3-aminophenyl)(pyridin-2-yl)methanol (43c) (0.983 g,3.50 mmol) in N,N-dimethylformamide (30 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.983 g, 3.50 mmol), N-ethyl-N-isopropylpropan-2-amine (4.90 mL, 28.1mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(1.676 g, 3.52 mmol) at room temperature. The reaction mixture wasstirred at 25° C. for 13 h and diluted with ethyl acetate (200 mL). Thereaction mixture was washed with water (2×100 mL), brine (75 mL), driedover anhydrous MgSO₄, filtered and concentrated in vacuum to dryness.The residue obtained was purified by flash column chromatography [silicagel 12 g, eluting with hexanes/ethyl acetate (1:0 to 0:1) to afford1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43d) (1.049g, 65%) as a off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 8.44 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.16 (dd, J=2.1, 1.4Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz,1H), 7.81-7.65 (m, 4H), 7.59-7.52 (m, 2H), 7.30-7.15 (m, 3H), 6.16 (d,J=4.0 Hz, 1H), 5.68 (d, J=4.0 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.95; MS (ES+): 464.2 (M+1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43e)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoro-methyl)-1H-pyrazole-5-carboxamide(43d) (0.48 g, 1.036 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.240 mL, 3.29 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was quenched with triethylamine (1.3 mL, 9.33 mmol) and stirred at room temperature for 1 h. Tothe chloro compound was added cyclopropylmethanol (8.00 mL, 97 mmol),triethyl amine (1.300 mL, 9.33 mmol) and concentrated in vacuum toremove most of dichloromethane. Triethyl amine (1.3 mL, 9.33 mmol) wasadded to reaction mixture and heated at 70° C. for 14 h and 100° C. for6 h. The reaction mixture was diluted with ethyl acetate and filtered.The filtrate was concentrated in vacuum and the residue was purified byflash column chromatography [silica gel eluting with hexanes/ethylacetate (1:0 to 2:1)] to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43e) (231 mg, 43%) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.51 (s, 1H), 8.29 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.00 (t, J=1.8 Hz,1H), 7.89-6.95 (m, 11H), 5.30 (s, 1H), 3.11 (d, J=6.8 Hz, 2H), 0.98-0.80(m, 1H), 0.38-0.21 (m, 2H), 0.08-−0.08 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.97; MS (ES+): 540.2 (M+23).

Step-5: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43f)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43e) (30 mg, 0.058 mmol) in MeOH (2 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (3.0 mg, 0.013 mmol) followed by sodiumborohydride (14.00 mg, 0.363 mmol) over a period of 5 min. the reactionmixture was stirred at room temperature for 1 h quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.015 mL, 0.133 mmol) stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (100 mL), washed with water (50mL). The aqueous phase was extracted again with ethyl acetate (50 mL).The organic extracts were combined washed with brine (50 mL), dried overMgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel 4 g, eluting withchloroform/methanol (1:0 to 9:1)] to afford Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43f) (14 mg, 46%) as a off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H), 8.48-8.44 (m, 1H), 7.93-7.04 (m, 12H), 5.46 (s, 1H), 3.77(s, 2H), 1.14-0.99 (m, 1H), 0.53-0.41 (m, 2H), 0.20-0.11 (m, 2H); ¹H NMR(300 MHz, DMSO-d₆, with D₂O exchange) δ 8.48-8.43 (m, 1H), 7.91-7.03 (m,12H), 5.46 (s, 1H), 3.77 (s, 2H), 3.28 (d, J=6.8 Hz, 2H), 1.14-0.96 (m,1H), 0.53-0.43 (m, 2H), 0.22-0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.73; MS (ES+): 522.3 (M+1).

To a solution of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43f) (193 mg, 0.37 mmol) in acetone (10 mL) was added conc. HCl (0.123mL, 1.480 mmol) and concentrated in vacuum to dryness. The residue wasdried in vacuum to remove excess HCl and dissolved in IPA (2 mL) withheating to solubilize. To the homogenous solution was added ether (40mL) and heated at reflux for 30 mins. After cooling to room temperaturethe solid obtained was collected by filtration, washed with ether anddried under vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (43f) (0.227 g, 0.382 mmol, 103% yield) as a whitesolid; ¹H NMR (300 MHz, Deuterium Oxide) δ 8.54-8.48 (m, 1H), 8.25 (td,J=8.0, 1.6 Hz, 1H), 7.72 (ddd, J=7.6, 5.8, 1.3 Hz, 1H), 7.67 (d, J=8.1Hz, 1H), 7.44 (t, J=2.5 Hz, 4H), 7.42-7.35 (m, 1H), 7.34-7.24 (m, 3H),7.14 (dt, J=7.0, 1.8 Hz, 1H), 5.82 (s, 1H), 4.07 (s, 2H), 3.46-3.31 (m,1H), 3.28 (m, 1H), 0.99-0.88 (m, 1H), 0.41-0.25 (m, 2H), 0.07-−0.07 (m,2H); ¹⁹F NMR (282 MHz, D₂O) 6-62.34; MS (ES−) 520.3 (M−1); Analysiscalculated for C₂₈H₂₆F₃N₅O₂.1.9HCl.H₂O: C, 55.24; H, 4.95; Cl, 11.06; N,11.50; Found: C, 55.59; H, 5.19; Cl, 10.91; N, 10.83.

Step-6: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43g) and(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43h)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43f) (158 mgs) was separated by chiral preparative HPLC using CHIRALPAKAD-H, 5μ, 4.6×250 mm chiral column, flow rate 1 mL/min, Solvent: 90%Hexane/10% EtOH/0.1% DEA, UV=254 nM, to furnish:

-   -   1.        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (43g) (0.066 g, 98.2% ee, Rt=10.432 min. This product was        repurified by flash column chromatography (silica gel 12 g,        eluting 0-25% methanol in chloroform for 13 mins) to afford 50        mgs pure        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (43g); ¹H NMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 8.50-8.43 (m,        1H), 7.81 (td, J=7.7, 1.8 Hz, 1H), 7.65 (t, J=1.8 Hz, 1H),        7.61-7.49 (m, 4H), 7.47-7.38 (m, 2H), 7.34-7.23 (m, 3H),        7.19-7.10 (m, 1H), 5.46 (s, 1H), 3.78 (s, 2H), 3.28 (dd, J=6.8,        1.2 Hz, 2H), 2.37-2.09 (m, 2H), 1.15-0.98 (m, 1H), 0.56-0.33 (m,        2H), 0.27-0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.71; MS        (ES+) 522.3 (M+1); (ES−) 556.3 (M+Cl); Optical Rotation −11.04        (MeOH, 2.5); Analysis calculated for C₂₈H₂₆F₃N₅O₂.0.5H₂O: C,        63.39; H, 5.13; N, 13.20; Found: C, 63.18; H, 5.13; N, 12.83;        Chiral purity checked by performing chiral HPLC using CHIRALPAK        AD-H, 5μ, 25 cm, 0.8 mL/min, Solvent: 75% Hexane/24% EtOH/0.1%        TEA, UV=260 nM, 14 min run time Rt=6.157 min (peak-1, 43g, 100%)        9.32 (peak-2, 43h, 0%).    -   2.        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (43h) (0.071 g, 98.8% ee, Rt=18.373 min). This product was        repurified by flash column chromatography (silica gel 12 g,        eluting 0-25% methanol in chloroform for 13 mins) to afford 40        mgs pure        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (43h); ¹H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.37-8.24 (m,        1H), 7.64 (td, J=7.7, 1.8 Hz, 1H), 7.52-7.45 (m, 1H), 7.44-7.32        (m, 4H), 7.31-7.21 (m, 2H), 7.19-7.05 (m, 3H), 6.98 (d, J=7.6        Hz, 1H), 5.29 (s, 1H), 3.61 (s, 2H), 1.00-0.79 (m, 1H),        0.44-0.18 (m, 2H), 0.13-−0.14 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −60.71; MS (ES+) 522.3 (M+1); (ES−) 556.3 (M+Cl);        Analysis calculated for C₂₈H₂₆F₃N₅O₂.0.75H₂O: C, 62.85; H, 5.18;        N, 13.09; Found: C, 63.17; H, 5.24; N, 12.70; Optical        Rotation+11.51 (MeOH, 2.05); Chiral purity checked by performing        chiral HPLC using CHIRALPAK AD-H, 5μ, 25 cm, 0.8 mL/min,        Solvent: 75% Hexane/24% EtOH/0.1% TEA, UV=260 nM, 14 min run        time Rt=6.157 min (peak-1, 43g, 0% ee) 9.313 (peak-2, 43h, 100%        ee).

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44c);(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44d) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44e) Step-1: Preparation of1-(3-Cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44a)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.463 g, 1.648 mmol) in DMF (10 mL) was added(3-aminophenyl)(pyridin-3-yl)methanol (31d) (0.33 g, 1.648 mmol)N-ethyl-N-isopropylpropan-2-amine (1.435 mL, 8.24 mmol) andbromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop) (0.922 g,1.978 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 37 h under nitrogen atmosphere. The reaction wasdiluted with water (25 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layer was washed with brine (50 mL), dried,filtered, and evaporated to dryness. The residue obtained was purifiedby flash column chromatography [silica gel 40 g, eluting with ethylacetate in hexanes from 0-100%] to furnish1-(3-Cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44a) (0.653 g, 1.409 mmol, 86% yield) as a yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 10.67 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1.7Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90(ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.77-7.64 (m, 4H), 7.62-7.52 (m, 1H),7.37-7.25 (m, 2H), 7.21-7.14 (m, 1H), 6.15 (d, J=3.9 Hz, 1H), 5.77 (d,J=4.0 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES−) 462.2(M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44b)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoro-methyl)-1H-pyrazole-5-carboxamide(44a) (0.24 g, 0.518 mmol) in dichloromethane (10 mL) at 0° C. was addedthionyl chloride (0.12 mL, 1.647 mmol) and allowed to warm to roomtemperature over 3 h. The reaction mixture was quenched with triethylamine (0.22 mL, 1.58 mmol), stirred at room temperature for 1 h, addedcyclopropylmethanol (5.00 mL, 60.4 mmol), triethylamine (0.5 mL, 3.59mmol), concentrated to remove most of dichloromethane followed byaddition of more triethylamine (0.5 mL, 3.59 mmol). The reaction mixturewas heated at 70° C. for 2 h, 100° C. for 6 h and concentrated in vacuumto dryness. The residue obtained was purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to1:1)] to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44b) (124 mg, 46%) as a light yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 8.60-8.55 (m, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 8.17 (t,J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1Hz, 1H), 7.78-7.58 (m, 5H), 7.42-7.28 (m, 2H), 7.20-7.13 (m, 1H), 5.56(s, 1H), 3.28-3.24 (m, 2H), 1.13-0.97 (m, 1H), 0.54-0.41 (m, 2H),0.20-0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS (ES+): 518.3(M+1).

Step-3: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44c)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44b) (108 mg, 0.209 mmol) in MeOH (6 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (11.00 mg, 0.046 mmol) followed byportionwise addition of Sodium Borohydride (50 mg, 1.296 mmol) over aperiod of 5 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.05 mL,1.296 mmol) followed by stirring for additional 0.5 h.

The reaction mixture was concentrated in vacuum to dryness and theresidue obtained was dissolved in ethyl acetate (150 mL) and water (75mL). The aqueous layer was separated extracted with ethyl acetate (75mL). The combined extracts were washed with brine (75 mL), dried overMgSO₄ filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica gel twice with 4 g,eluting with chloroform/methanol (1:0 to 9:1)] to furnish Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44c) (0.042 g, 39%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.74(s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.75-7.13(m, 11H), 5.55 (s, 1H), 3.80 (s, 2H), 3.26 (dd, J=6.8, 2.5 Hz, 2H),1.12-1.00 (m, 1H), 0.53-0.35 (m, 2H), 0.22-0.06 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.74; MS (ES+): 522.3 (M+1).

Step-4: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44d) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44e)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(44c) (231 mgs) was separated using chiral preparative HPLC usingCHIRALPAK AD-H, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 80%Hexane/20% EtOH/0.1% DEA, UV=254 nM to furnish:

-   -   1.        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (44d) (0.0791 g, Rt=6.28 min, 99.8% ee). This product was        repurified by flash column chromatography (silica gel 12 g,        eluting 0-25% methanol in chloroform for 13 mins at a flow rate        of 50 mL/min) to afford pure        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (44d) (60 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ        10.74 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.46 (dd, J=4.8, 1.7 Hz,        1H), 7.75-7.26 (m, 11H), 7.21-7.11 (m, 1H), 5.55 (s, 1H), 3.77        (s, 2H), 3.26 (dd, J=6.8, 2.3 Hz, 2H), 1.16-0.96 (m, 1H),        0.56-0.37 (m, 2H), 0.27-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −60.71; MS (ES+) 522.3 (M+1); (ES−) 520.3 (M+1); Optical        rotation=+10.86 (methanol, 3.0). Chiral purity checked by        performing chiral HPLC using AD-H column 76/24/0.1        (Hexane/ethanol/TEA) 0.8 mL/min UV 260 nM, 14 mins run time        (Temp 25° C.). Rt=6.817 (100%, peak-1, 44d), Rt=10.043 (0%,        peak-2, 44e); Analysis calculated for C₂₈H₂₆F₃N₅O₂.0.75H₂O: C,        62.85; H, 5.18; N, 13.09; found: C, 62.90; H, 5.11; N, 12.73.    -   2.        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (44e) (0.083 g, Rt=8.961 min, 99.0% ee). This product was        repurified by flash column chromatography (silica gel 12 g,        eluting 0-25% methanol in chloroform for 13 mins at a flow rate        of 50 mL/min) to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (44e) (60 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ        10.74 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.46 (dd, J=4.8, 1.7 Hz,        1H), 7.70 (dt, J=8.0, 2.0 Hz, 1H), 7.64 (t, J=1.8 Hz, 1H),        7.61-7.50 (m, 3H), 7.43 (d, J=2.7 Hz, 1H), 7.40 (d, J=8.6 Hz,        1H), 7.37-7.28 (m, 3H), 7.16 (d, J=7.6 Hz, 1H), 5.55 (s, 1H),        3.77 (s, 2H), 3.25 (dd, J=6.9, 2.4 Hz, 2H), 1.16-0.96 (m, 1H),        0.56-0.34 (m, 2H), 0.27-0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −60.71; MS (ES+) 522.3 (M+1); (ES−) 520.3 (M+1); Optical        rotation=−11.33 (methanol, 3.0); Chiral purity checked by        performing chiral HPLC using AD-H column 76/24/0.1        (Hexane/ethanol/TEA) 0.8 mL/min UV 260 nM, 14 mins run time        (Temp 25° C.). R_(t)=6.817 (0% ee, peak-1, 44d), R_(t)=9.943        (100%, peak-2, 44e); Analysis calculated for        C₂₈H₂₆F₃N₅O₂.0.75H₂O: C, 62.85; H, 5.18; N, 13.09; Found: C,        62.88; H, 5.12; N, 12.70.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(45g) Step-1: Preparation of(E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (45b)

To a stirred solution of 1-(pyridin-2-yl)ethanone (45a) (1.516 mL, 13.27mmol) in methanol (100 mL) cooled to 0° C. was addedcyclopropanecarboxaldehyde (1.5 mL, 19.90 mmol) and aqueous potassiumhydroxide (1N, 2.65 mL, 2.65 mmol). The reaction was allowed to warm toroom temperature overnight. The reaction was acidified with 1 Nhydrochloric acid and concentrated in vacuum to remove methanol. Thecrude residue was dissolved in ethyl acetate (100 mL) washed with sodiumcarbonate solution, water (2×50 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography (silicagel, 12 g, eluting with ethyl acetate in hexanes 0to 100%) to afford afford pure(E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (45b) (479 mg,20.85%), which was good to be used as such for next, MS (ES+) 174.1(M+1).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45c)

To Pd/C (10%, 0.230 g, 0.216 mmol) in methanol (50 mL) was added(E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (45b) (1.5 g, 8.66mmol) and hydrogenated at 60 psi for 2 h. The reaction mixture wasfiltered through Celite and filtrate concentrated in vacuum. The cruderesidue was purified by flash column chromatography (silicagel, 12 g,eluting with CMA 80 in chloroform 0-100%) to afford3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45c) (1.02 g, 66.5%) as anoil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (ddd, J=4.9, 1.8, 0.9 Hz, 1H),7.76 (td, J=7.7, 1.8 Hz, 1H), 7.46 (dt, J=8.1, 1.2 Hz, 1H), 7.22 (ddd,J=7.5, 4.8, 1.2 Hz, 1H), 5.29 (d, J=5.0 Hz, 1H), 4.58 (dt, J=8.2, 4.8Hz, 1H), 1.83 (dddd, J=13.6, 9.2, 7.2, 4.6 Hz, 1H), 1.66 (dtd, J=13.3,8.1, 6.7 Hz, 1H), 1.22 (dt, J=8.1, 6.5 Hz, 2H), 0.73-0.58 (m, 1H),0.41-0.29 (m, 2H), 0.03-−0.06 (m, 2H); MS (ES+) 200.1 (M+23).

Step-3: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (45d)

To a stirred solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45c)(1 g, 5.64 mmol) in dichloromethane (10 mL) at 0° C. was added NaHCO₃(1.422 g, 16.93 mmol) and Dess-MartinPeriodinane (4.79 g, 11.28 mmol).The reaction mixture was stirred at 0° C. for 30 minutes and warmed toroom temperature in 15 mins. The reaction was stirred at roomtemperature for 1 hr and quenched by adding aqueous saturated sodiumbicarbonate (25 mL), extracted with dichloromethane (2×50 mL). Theorganic layers were combined, washed with water (2×25 mL), brine (25mL), dried, filtered and concentrated in vacuum. The crude residue waspurified by column chromatography (silicagel, 12 g, eluting with 0-1005ethyl acetate in hexane) to afford3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (45d) (836 mg, 85%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (ddd, J=4.8, 1.7, 1.0 Hz, 1H),8.13-7.87 (m, 2H), 7.77-7.56 (m, 1H), 3.26 (t, J=7.3 Hz, 2H), 1.54 (q,J=7.2 Hz, 2H), 0.83-0.67 (m, 1H), 0.45-0.32 (m, 2H), 0.08-0.01 (m, 2H);MS (ES+) 176.1 (M+1).

Step-4: Preparation of1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45e)

To a stirred solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one(45d) (400 mg, 2.283 mmol) in tetrahydrofuran (15 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (2.283 mL,2.283 mmol) at 0° C. Reaction was allowed to warm to room temperatureand stirred for 2 h. The reaction was quenched with ammonium chloridesolution (25 mL), extracted with ethyl acetate (2×50 mL). the organiclayers were combined, washed with water (2×25 mL), brine (25 mL), dried,filtered and concentrated in vacuum. The crude residue was purified byflash column chromatography (silicagel, 25 g eluting with CMA 80 inchloroform 0-100%) to afford1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45e) (365mg, 59.6%). This was pure enough to be used as such in next step; ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.70 (ddd,J=8.0, 7.3, 1.8 Hz, 1H), 7.58 (dt, J=8.0, 1.1 Hz, 1H), 7.17 (ddd, J=7.4,4.8, 1.2 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H), 6.75 (t, J=1.9 Hz, 1H), 6.64(ddd, J=7.7, 1.8, 1.1 Hz, 1H), 6.31 (ddd, J=7.8, 2.2, 1.0 Hz, 1H), 5.51(s, 1H), 4.93 (s, 2H), 2.36 (ddd, J=13.3, 11.1, 5.2 Hz, 2H), 1.17-0.89(m, 2H), 0.60 (dqd, J=11.9, 7.0, 3.9 Hz, 1H), 0.39-0.26 (m, 2H),−0.04-−0.17 (m, 2H); MS (ES+) 291.2 (M+23).

Step-5: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(45f)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(297 mg, 1.056 mmol) in DMF (6 mL) was added1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45e) (340mg, 1.267 mmol), N-ethyl-N-isopropylpropan-2-amine (1.471 mL, 8.45 mmol)and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP, 541mg, 1.161 mmol) at room temperature and stirred at 25° C. for 16 h. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (100 mL, 50 mL). The organic layers were combined and dried overanhydrous MgSO₄, filtered, concentrated under reduced pressure todryness. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with CMA 80 in chloroform0-100%) to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(45f) (328 mg, 58.4%); MS (ES+) 532.2 (M+1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(45g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(45f) (300 mg, 0.564 mmol) in methanol (25 mL) at 0° C. was addednickel(II) chloride hexahydrate (29.2 mg, 0.123 mmol), To this sodiumtetrahydroborate (133 mg, 3.53 mmol) was added in small portions over aperiod of 15 minutes. The reaction was stirred for 15 minutes, quenchedby adding N1-(2-aminoethyl)ethane-1,2-diamine (0.135 mL, 1.298 mmol) andstirred for 30 minutes at room temperature. The reaction mixture wasconcentrated in vacuum to remove methanol. The residue was adsorbed onsilicagel and purified twice by flash column chromatography (silica gel,12 g, eluting with CMA 80 in chloroform 0 to 100%) and (silica gel 2×4g, eluting with methanol in chloroform 0 to 30%) to afford1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(70 mg, 0.131 mmol, 23.16% yield) as a colorless solid; ¹HNMR (300 MHz,DMSO-d₆) δ 10.75 (s, 1H, D₂O exchangeable), 8.68-8.48 (m, 1H), 7.87-7.77(m, 2H), 7.73-7.68 (m, 1H), 7.67 (s, 1H), 7.65-7.60 (m, 2H), 7.54-7.47(m, 2H), 7.40 (ddd, J=7.5, 3.9, 1.9 Hz, 1H), 7.37-7.31 (m, 1H),7.31-7.25 (m, 2H), 5.84 (s, 1H, D₂O exchangeable), 3.87 (s, 2H),2.56-2.44 (m, 2H), 2.33 (s, 2H, D₂O exchangeable), 1.12 (m, 2H),0.78-0.56 (m, 1H), 0.49-0.32 (m, 2H), −0.01 (m, 2H); MS (ES+) 536.3(M+1), (ES−) 534.1 (M−1), 570.0 (M+23).

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46g),(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46h) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46i) Step-1: Preparation of (E)-3-cyclopropyl-1-phenylprop-2-en-1-one(46b)

To a stirred solution of diethyl 2-oxo-2-phenylethylphosphonate (46a)(1.8 g, 7.02 mmol) in acetonitrile (50 mL) was added LiBr (0.610 g, 7.02mmol) and diisopropylethylamine (DIPEA, 2.454 mL, 14.05 mmol),cyclopropanecarboxaldehyde (0.529 mL, 7.02 mmol) was added drop-wise atroom temperature and reaction stirred at room temperature for 16 h. Thereaction mixture was filtered through Celite and concentrated in vacuum.The crude residue was purified by flash column chromatography (silicagel, 24 g, eluting with ethyl acetate in hexanes 0-100%) to afford(E)-3-cyclopropyl-1-phenylprop-2-en-1-one (46b) (315 mg, 26.0%) as anoil; ¹H NMR (300 MHz, Chloroform-d) δ 8.00-7.87 (m, 2H), 7.63-7.42 (m,3H), 7.03 (d, J=15.1 Hz, 1H), 6.56 (dd, J=15.1, 10.3 Hz, 1H), 1.83-1.59(m, 1H), 1.14-0.94 (m, 2H), 0.84-0.65 (m, 2H); MS (ES+): 173.1 (M+1).

Step-2: Preparation of 3-cyclopropyl-1-phenylpropan-1-ol (46c)

To a suspension of Pd/C (10%, 97 mg, 0.091 mmol) in ethyl acetate (35mL) was added (E)-3-cyclopropyl-1-phenylprop-2-en-1-one (46b) (315 mg,1.829 mmol) and hydrogenated at 60 psi for 1 h. The reaction wasfiltered through Celite and concentrated in vacuum. The crude residuewas purified by flash column chromatography (silica gel, 24 g, elutingwith ethyl acetate in hexanes 0-30%) to afford (46c) (260 mg, 81%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.14 (m, 5H), 5.10 (d, J=4.4 Hz,1H), 4.52 (ddd, J=7.3, 5.7, 4.4 Hz, 1H), 1.76-1.55 (m, 2H), 1.35-1.08(m, 2H), 0.72-0.59 (m, 1H), 0.43-0.28 (m, 2H), −0.04 (ddt, J=5.2, 4.2,2.0 Hz, 2H); MS (ES+): 199.1 (M+Na).

Step-3: Preparation of 3-cyclopropyl-1-phenylpropan-1-one (46d)

To a stirred solution of 3-cyclopropyl-1-phenylpropan-1-ol (46c) (0.250g, 1.418 mmol) in dichloromethane (30 mL) at 0° C. was added sodiumbicarbonate (0.336 g, 4.00 mmol), Dess-Martin periodinane (1.191 g, 2.67mmol) and stirred for 30 mins. The reaction mixture was warmed to roomtemperature in 15 mins, filtered through a Celite pad and concentratedin vacuum. The crude residue was purified by flash column chromatography(silica gel, 24 g, eluting with ethyl acetate in hexanes 0-30%) toafford 3-cyclopropyl-1-phenylpropan-1-one (46d)(150 mg, 60.7%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.98-7.87 (m, 2H), 7.63-7.53 (m, 1H),7.47 (ddt, J=8.2, 6.6, 1.2 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H), 1.46 (q,J=7.1 Hz, 2H), 0.81-0.59 (m, 1H), 0.41-0.24 (m, 2H), 0.04-−0.05 (m, 2H);MS (ES+): 197.1 (M+Na).

Step-4: Preparation of1-(3-aminophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (46e)

To a stirred solution of 3-cyclopropyl-1-phenylpropan-1-one (46d) (150mg, 0.861 mmol) in tetrahydrofuran (10 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (1.722 mL,1.722 mmol) at 0° C. The reaction was allowed to stir for 2 h at 0° C.,quenched with saturated aqueous ammonium chloride solution (25 mL) andextracted with ethyl acetate (2×50 mL). The organic layers werecombined, washed with water (2×25 mL), brine (25 mL), dried, filteredand concentrated in vacuum. The crude residue was purified by flashcolumn chromatography (silica gel, 24 g, eluting with ethyl acetate inhexanes 0-100%) to afford1-(3-aminophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (46e) (180 mg, 78%);¹H NMR (300 MHz, DMSO-d6) δ 7.44-7.33 (m, 2H), 7.30-7.18 (m, 2H),7.17-7.07 (m, 1H), 6.88 (t, J=7.8 Hz, 1H), 6.68 (t, J=1.9 Hz, 1H), 6.55(dt, J=7.7, 1.3 Hz, 1H), 6.32 (ddd, J=7.8, 2.2, 0.9 Hz, 1H), 5.21 (s,1H), 4.93 (s, 2H), 2.23 (t, J=8.2 Hz, 2H), 1.07 (ddd, J=28.3, 13.6, 6.4Hz, 2H), 0.61 (dd, J=11.7, 6.1 Hz, 1H), 0.40-0.26 (m, 2H), −0.09 (td,J=5.2, 3.5 Hz, 2H); MS (ES+): 290.2 (M+Na), MS (ES−): 266.1 (M−1).

Step-5: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46f)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.008 g, 3.58 mmol) in N,N-dimethylformamide (20 mL) was added1-(3-aminophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (46e) (1.15 g, 4.30mmol), N-ethyl-N-isopropylpropan-2-amine (5.01 mL, 28.7 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 1.838 g,3.94 mmol) at room temperature. The reaction mixture was stirred at 25°C. for 16 h quenched with water (100 mL) and extracted with ethylacetate (2×150 mL). The organic layers were combined dried overanhydrous MgSO₄, filtered, and concentrated in under reduced pressure todryness. The residue was purified by flash column chromatography (silicagel 25 g, eluting with hexanes in ethyl acetate/hexanes from 0-40 to100%) to afford1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46f) (1.6 g, 84%) which was taken as such for next step; ¹H NMR (300MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.21-8.13 (m, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.90 (ddd, J=8.3, 2.3, 1.2 Hz, 1H), 7.78-7.66 (m, 3H),7.62-7.54 (m, 1H), 7.46-7.36 (m, 2H), 7.29-7.23 (m, 3H), 7.19-7.14 (m,2H), 5.49 (s, 1H), 2.36-2.24 (m, 2H), 1.08 (d, J=8.7 Hz, 2H), 0.63 (s,1H), 0.43-0.26 (m, 2H), −0.04-−0.14 (m, 2H); MS (ES−) 529.2 (M−1).

Step-6: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46f) (0.77 g, 1.451 mmol) in methanol (75 mL) at 0° C. was addednickel(II) chloride hexahydrate (0.075 g, 0.316 mmol) followed by sodiumtetrahydroborate (0.549 g, 14.51 mmol) in small portions over a periodof 15 mins. The reaction was stirred for 15 mins, quenched by addingN1-(2-aminoethyl)ethane-1,2-diamine (0.076 mL, 0.737 mmol), stirred foradditional 30 mins at room temperature and concentrated in vacuum toremove methanol. The reaction mixture was diluted water (25 mL) andextracted with ethyl acetate (3×50 mL). the organic layers were combinedwashed with water (2×20 mL), brine (20 mL), dried and concentrated. Thecrude residue was purified by flash column chromatography (silica gel 12g, eluting with CMA 80 in chloroform 0 100%) to afford Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46g) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H,D₂O exchangeable), 7.71-7.66 (m, 1H), 7.60-7.50 (m, 3H), 7.45-7.38 (m,4H), 7.34-7.11 (m, 6H), 5.48 (s, 1H, D₂O exchangeable), 3.78 (s, 2H),2.30 (dd, J=10.5, 5.8 Hz, 4H, 2H D₂O exchangeable), 1.06 (dd, J=10.7,5.7 Hz, 2H), 0.62 (q, J=9.4, 7.3 Hz, 1H), 0.41-0.25 (m, 2H), −0.08 (tt,J=5.4, 2.8 Hz, 2H); Mass spec (ES+) 535.3 (M+1), 557.3 (M+23), (ES−)533.3 (M−1), 569.3 (M+35).

Step-7: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46h) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46i)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46g) (367 mg) was was separated using chiral preparative HPLC usingPurified by chiral preparative HPLC using CHIRALPAK IC, 5μ, 4.6×250 mm,flow rate 1 mL/min, Solvent: 50% Hexane/49% DCM/1% EtOH/0.1% DEA, UV=280nM, 25° C., to furnish:

-   -   1. Peak-1 corresponding to        (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (46h) (101.9 mg, 97.1% ee); Chiral HPLC (Rt=8.975 min, 98.5689%        peak-, 1 compound 46h), (Rt=10.075 min, 1.4311% peak-2, compound        46i). This compound was repurified by flash column        chromatography (silica gel 4 g, eluting 0-25-100% CMA-80 in        chloroform for 25 mins) to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (46h) (84 mg, 91.49 ee); Optical rotation: [α]_(D)=+1.674        [CH₃OH]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H, D₂O        exchangeable), 7.68 (s, 1H), 7.60-7.50 (m, 3H), 7.48-7.37 (m,        4H), 7.35-7.21 (m, 4H), 7.16 (q, J=7.1 Hz, 2H), 5.48 (s, 1H, D₂O        exchangeable), 3.78 (s, 2H), 2.39-2.21 (m, 2H), 1.14-1.00 (m,        2H), 0.61 (h, J=6.4 Hz, 1H), 0.34 (dq, J=8.1, 4.0 Hz, 2H), −0.08        (t, J=4.8 Hz, 2H); MS (ES+) 535.3 (M+1), (ES−) 533.3 (M−1);        Analysis calculated for C₃₀H₂₉F₃N₄O₂.0.75H₂O: C, 65.74; H, 5.61;        N, 10.22; Found C, 66.10; H, 5.82; N, 9.78.    -   2. Peak-2 corresponding to        (−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (46i) (98.8 mg, 97.5% ee); Chiral HPLC (Rt=9.039 min, 1.2741%        peak-1, compound 46h) (Rt=10.052, 98.7259% peak-2, compound        46i). This compound was repurified by flash column        chromatography (silica gel 12 g, eluting 0-30% MeOH in        chloroform for 25 mins) to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (46i) (45 mgs, 87.3% ee) as a white solid; Optical rotation:        [α]_(D)=(−)2.00 [CH₃OH, 0.505]; ¹H NMR (300 MHz, DMSO-d₆) δ        10.66 (s, 1H, D₂O exchangeable), 7.72-7.66 (m, 1H), 7.61-7.50        (m, 3H), 7.47-7.37 (m, 4H), 7.35-7.11 (m, 6H), 5.48 (s, 1H, D₂O        exchangeable), 3.78 (s, 2H), 2.38-2.23 (m, 2H), 1.36-1.00 (m,        3H), 0.62 (ddt, J=10.5, 7.3, 3.7 Hz, 1H), 0.47-0.30 (m, 2H),        −0.08 (td, J=5.4, 3.8 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.70; MS (ES+) 557.3 (M+Na); Analysis calculated for        C₃₀H₂₉F₃N₄O₂.0.25H₂O: C, 66.84; H, 5.52; N, 10.39; Found: C,        66.90; H, 5.74; N, 10.04.

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47f);(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47g) and(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47h) Step-1: Preparation of(E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (47b)

To a stirred solution of 3-acetylpyridine (47a) (9.07 mL, 83 mmol) inmethanol (200 mL) cooled to 0° C. was added cyclopropanecarboxaldehyde(9.95 mL, 132 mmol) and aqueous potassium hydroxide (1N solution, 16.51mL, 16.51 mmol). The reaction was allowed to warm to room temperatureovernight. The reaction was acidified with 1 N hydrochloric acid andconcentrated in vacuum to remove methanol. The crude residue wasdissolved in ethyl acetate (300 mL) washed with sodium carbonatesolution, water (2×100 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography (silicagel, 80 g, eluting with ethyl acetate in hexanes 0to 100%) to afford (E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one(47b) (5.99 g, 41.9%); ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (td, J=2.7, 0.9Hz, 1H), 8.80 (ddd, J=4.9, 3.3, 1.7 Hz, 1H), 8.36-8.27 (m, 1H), 7.57(ddt, J=8.0, 4.8, 1.2 Hz, 1H), 7.28 (d, J=15.1 Hz, 1H), 6.58 (dd,J=15.1, 10.3 Hz, 1H), 1.80 (dddd, J=12.5, 10.4, 7.8, 4.5 Hz, 1H),1.08-0.99 (m, 2H), 0.85-0.76 (m, 2H); MS (ES+) 196.1 (M+Na).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c)

To a stirred solution of(E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (47b) (5.93 g, 34.2mmol) in benzene (150 mL) was added tributylstannane (18.42 mL, 68.5mmol) and heated to reflux. The reaction was stirred at reflux for 5 hand cooled to room temperature. Benzene was evaporated and the residuewas purified by flash column chromatography (silica gel, 80 g, elutingwith ethyl acetate in hexanes 0 to 100%) to afford3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (5.29 g, 88%); ¹H NMR(300 MHz, DMSO-d₆) δ 9.07 (dd, J=2.3, 0.9 Hz, 1H), 8.72 (dd, J=4.8, 1.7Hz, 1H), 8.24 (ddd, J=8.0, 2.4, 1.8 Hz, 1H), 7.50 (ddd, J=8.0, 4.9, 0.9Hz, 1H), 3.09 (t, J=7.2 Hz, 2H), 1.47 (q, J=7.1 Hz, 2H), 0.70 (dddd,J=12.0, 8.1, 5.1, 2.2 Hz, 1H), 0.40-0.21 (m, 2H), 0.06-−0.05 (m, 2H).

Step-3: Preparation of1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d)

To a stirred solution of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one(47c) (2 g, 11.41 mmol) in tetrahydrofuran (20 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (4.23 g,14.27 mmol) at 0° C. The reaction was allowed to come to roomtemperature for 12 h, quenched by adding ammonium chloride solution (25mL) and ethyl acetate (50 mL). The reaction was acidified withhydrochloric acid (10 mL, 3N) and stirred for 15 minutes and basifiedwith saturated potassium carbonate solution (20 mL), extracted withethyl acetate (3×100 mL). the organic layers were combined washed withwater (2×50 mL), brine (25 mL), dried and concentrated in vacuum. Thecrude residue was purified by by flash column chromatography (silicagel, 80 g, eluting with CMA 80 in chloroform) to afford1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d) (3.0g, 11.18 mmol, 98% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.59 (dd, J=2.4, 0.9 Hz, 1H), 8.38-8.31 (m, 1H), 7.74 (ddd,J=8.0, 2.4, 1.7 Hz, 1H), 7.27 (ddd, J=8.0, 4.7, 0.8 Hz, 1H), 6.91 (t,J=7.8 Hz, 1H), 6.69 (t, J=2.0 Hz, 1H), 6.61-6.51 (m, 1H), 6.35 (ddd,J=7.9, 2.2, 0.9 Hz, 1H), 5.46 (s, 1H, D₂O exchangeable), 4.98 (s, 2H,D₂O exchangeable), 2.35-2.18 (m, 2H), 1.21-0.94 (m, 2H), 0.62 (qt,J=7.2, 3.8 Hz, 1H), 0.41-0.28 (m, 2H), −0.07 (td, J=5.3, 3.7 Hz, 2H).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47e)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.148 g, 7.64 mmol) in N,N-dimethylformamide (46.1 mL, 596 mmol) wasadded 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d)(2.46 g, 9.17 mmol), N-ethyl-N-isopropylpropan-2-amine (10.64 mL, 61.1mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP,3.92 g, 8.40 mmol) at room temperature. The resulting reaction mixturewas stirred at 25° C. for 16 h. The reaction mixture was diluted withwater (200 mL) and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL), driedover anhydrous MgSO₄, filtered, and concentrated in under reducedpressure to dryness. The residue was purified by flash columnchromatography (silica gel 80 g, eluting with CMA 80 in chloroform0-100%) to afford1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47e) (3.63 g, 89%); ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.62 (d,J=2.3 Hz, 1H), 8.37 (dd, J=4.7, 1.6 Hz, 1H), 8.16 (t, J=1.9 Hz, 1H),8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H),7.82-7.66 (m, 4H), 7.65-7.55 (m, 1H), 7.38-7.06 (m, 3H), 5.74 (s, 1H),2.34 (t, J=8.1 Hz, 2H), 1.10 (t, J=6.1 Hz, 2H), 0.64 (s, 1H), 0.41-0.27(m, 2H), −0.06 (dd, J=5.8, 4.1 Hz, 2H); MS (ES−) 530.2 (M−1).

Step-5: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47f)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47e) (2.038 g, 3.83 mmol) in methanol (100 mL) at 0° C. was addednickel(II) chloride hexahydrate (1.139 g, 4.79 mmol) followed by sodiumtetrahydroborate (1.451 g, 38.3 mmol) in small portions over a period of15 minutes. The reaction was stirred for 30 minutes quenched withN1-(2-aminoethyl)ethane-1,2-diamine (3.18 mL, 30.7 mmol) and stirred for30 mins at room temperature. The reaction mixture was concentrated toremove methanol, diluted water (200 mL) and stirred for 30 minutes. Thesolid separated was collected by filtration. The solid was suspended inethanol (100 mL) and concentrated to remove water. The residue wasdissolved in methanol and purified by flash column chromatography(silica gel 80 g, eluting with CMA 80 in chloroform 0-50%) to affordRacemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47f) (575 mg, 1.074 mmol, 28.0% yield) as a colorless solid.

¹HNMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H, D₂O exchangeable), 8.62 (dd,J=2.4, 0.9 Hz, 1H), 8.37 (dd, J=4.7, 1.6 Hz, 1H), 7.77 (dt, J=8.0, 2.0Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.56 (d, J=6.6 Hz, 2H), 7.54-7.49 (m,1H), 7.47-7.37 (m, 2H), 7.34-7.27 (m, 2H), 7.24 (d, J=7.7 Hz, 1H), 7.19(dt, J=8.0, 1.5 Hz, 1H), 5.73 (s, 1H, D₂O exchangeable), 3.77 (s, 2H),2.42-2.27 (m, 2H), 2.04 (s, 2H, D₂O exchangeable), 1.09 (h, J=6.7, 6.3Hz, 2H), 0.73-0.54 (m, 1H), 0.44-0.28 (m, 2H), −0.07 (dd, J=4.8, 1.6 Hz,2H); Mass spec (ES+) 536.3 (M+1), (ES−) 534.3 (M−1), 570.4 (M+35).

Step-6: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47g) and(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47h)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(47f) (317 mgs) was separated by chiral preparative HPLC using CHIRALPAKAD-H, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 85% Hexane/15%EtOH/0.1% DEA, UV=254 nM, 25° C.; to furnish:

-   -   1. Peak-1 corresponding to        (−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47g) (0.193 g, 98.9% ee); Chiral HPLC (Rt=9.426 min, 99.4471%        peak-1 for 47g), (Rt=11.592, 0.5529% peak-2 for 47h); Peak-1 or        compound 47g was repurified by flash column chromatography        (silica gel 12 g, eluting 0-100% CMA-80 in chloroform for 13        mins) to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47g) (124 mgs pure Peak-1); Optical Rotation −4.87 (MeOH,        0.945); ¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.62 (dd,        J=2.5, 0.9 Hz, 1H), 8.37 (dd, J=4.7, 1.6 Hz, 1H), 7.81-7.74 (m,        1H), 7.70 (t, J=1.9 Hz, 1H), 7.60-7.54 (m, 2H), 7.51 (t, J=1.6        Hz, 1H), 7.46-7.38 (m, 2H), 7.33-7.27 (m, 2H), 7.24 (d, J=7.8        Hz, 1H), 7.19 (dt, J=7.9, 1.5 Hz, 1H), 5.72 (s, 1H), 3.77 (s,        2H), 2.41-2.27 (m, 2H), 1.94 (s, 2H), 1.13-1.06 (m, 2H), 0.63        (dt, J=8.4, 5.4 Hz, 1H), 0.40-0.30 (m, 2H), −0.03-−0.11 (m, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71. Free base of compound 47g        was dissolved in methanol and added (0.05 mL) of 2 N HCl in        methanol. The mixture was concentrated in vacuum to dryness to        furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47g) (105 mg, 98.93% ee) as a HCl salt; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.70 (s, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.38 (dd,        J=4.7, 1.6 Hz, 1H), 7.77 (dt, J=8.0, 2.0 Hz, 1H), 7.71 (t, J=1.9        Hz, 1H), 7.64-7.55 (m, 3H), 7.54-7.44 (m, 2H), 7.40 (dt, J=7.2,        2.1 Hz, 1H), 7.34-7.29 (m, 1H), 7.27 (d, J=7.5 Hz, 1H),        7.24-7.16 (m, 1H), 5.73 (s, 1H), 3.94 (s, 2H), 2.38-2.27 (m,        2H), 1.18-0.99 (m, 2H), 0.72-0.53 (m, 1H), 0.41-0.25 (m, 2H),        −0.07 (dt, J=5.5, 2.7 Hz, 2H); 19F NMR (282 MHz, DMSO-d₆) δ        −60.75; MS (ES+) 536.3 (M+1); (ES−) 570.3 (M+Cl); Chiral HPLC        purity check using CHIRALPAK AD-H, 0.8 mL/min, Solvent: 85%        Hexane/15% EtOH/0.1% TEA, UV=260 nM, 40° C.; Chiral HPLC        (Rt=13.443 min, 99.4653% for peak-1 compound 47g), (Rt=16.433,        0.5347% for peak-2 compound 47h); Analysis calculated for        C₂₉H₂₈F₃N₅O₂.0.75HCl: C, 61.88; H, 5.15; Cl, 4.72; N, 12.44;        Found: C, 62.02; H, 5.31; Cl, 4.55; N, 12.30    -   2. Peak-2 corresponding to        (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47h) (0.248 g, 94.25 ee); Chiral HPLC (Rt=9.347, 2.88% peak-1        for 47g) (Rt=11.47, 97.11% peak2 for 47h). Peak-2 or compound        47h was purified twice by flash column chromatography (silica        gel 24 gm and 12 g, eluting 0-100% CMA-80 in chloroform for 13        mins) to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47h) (105 mgs pure Peak-2) as free base; Optical Rotation+4.76        (MeOH, 0.84); ¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.62        (dd, J=2.4, 0.9 Hz, 1H), 8.37 (dd, J=4.7, 1.6 Hz, 1H), 7.77        (ddd, J=8.0, 2.4, 1.6 Hz, 1H), 7.70 (t, J=1.8 Hz, 1H), 7.56 (d,        J=6.4 Hz, 2H), 7.53-7.50 (m, 1H), 7.46-7.37 (m, 2H), 7.34-7.27        (m, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.22-7.16 (m, 1H), 5.72 (s,        1H), 3.77 (s, 2H), 2.34 (t, J=8.0 Hz, 2H), 1.99 (s, 2H), 1.08        (dt, J=13.2, 6.6 Hz, 2H), 0.72-0.55 (m, 1H), 0.43-0.28 (m, 2H),        −0.03-−0.12 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.71. Free        base of compound 47h was dissolved in methanol and added (0.05        mL) of 2 N HCl in methanol. The mixture was concentrated in        vacuum to dryness to furnish        (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (47h) (95 mg, 95.39% ee) as HCl salt; ¹H NMR (300 MHz, DMSO-d₆)        δ 10.78 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.44 (dd, J=4.7, 1.6        Hz, 1H), 7.84 (dt, J=8.0, 2.0 Hz, 1H), 7.78 (t, J=1.9 Hz, 1H),        7.71-7.51 (m, 5H), 7.47 (dt, J=7.6, 2.0 Hz, 1H), 7.40-7.24 (m,        3H), 5.80 (s, 1H), 4.02 (s, 2H), 2.46-2.34 (m, 2H), 1.22-1.05        (m, 2H), 0.78-0.60 (m, 1H), 0.48-0.30 (m, 2H), −0.01 (dt, J=5.5,        2.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.74; MS (ES+) 536.3        (M+1); (ES−) 570.3 (M+Cl); Chiral HPLC purity check using        CHIRALPAK AD-H, 0.8 mL/min, Solvent: 85% Hexane/15% EtOH/0.1%        TEA, UV=260 nM, 40° C.; Chiral HPLC (R_(t)=13.617 min, 2.3061%        for peak-1 compound 47g), (Rt=16.35, 97.6939% for peak-2        compound 47h); Analysis calculated for        C₂₉H₂₈F₃N₅O₂.0.65HCl.0.5H₂P: C, 61.29; H, 5.26; Cl, 4.06; N,        12.32; Found: C, 61.20; H, 5.30; Cl, 4.04; N, 12.05.

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48f);(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48g) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48h) Step-1: Preparation of(4-Fluoro-3-nitrophenyl)(pyridin-3-yl)methanol (48b)

A solution of 4-fluoro-3-nitrobenzaldehyde (48a) (4.2 g, 24.84 mmol) intetrahydrofuran (100 mL) was cooled to 0° C. and treated withpyridin-3-ylmagnesium bromide (99 mL, 24.84 mmol, 0.25 M solution in2-methyl THF), stirred at 0° C. for 3 h and room temperature for 14 h.The reaction mixture was quenched with saturated aqueous NH₄Cl (60 mL)and extracted with EtOAc (2×75 mL). The organic extracts were combinedwashed with brine (50 mL), dried over anhydrous MgSO₄, filtered, andevaporated to dryness. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish(4-Fluoro-3-nitrophenyl)(pyridin-3-yl)methanol (48b) (3.104 g, 50%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=2.2 Hz,1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 8.20 (dd, J=7.4, 2.3 Hz, 1H), 7.79(ddt, J=15.0, 8.0, 2.2 Hz, 2H), 7.56 (dd, J=11.3, 8.7 Hz, 1H), 7.36(ddd, J=7.9, 4.7, 0.9 Hz, 1H), 6.45 (d, J=4.2 Hz, 1H, D₂O exchangeable),5.94 (d, J=4.2 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −121.35; MS (ES⁺):MS (ES+) 249.1 (M+1), MS (ES−) 495.1 (2M−1).

Step-2: Preparation of (3-amino-4-fluorophenyl)(pyridin-3-yl)methanol(48c)

To a stirred solution of (4-Fluoro-3-nitrophenyl)(pyridin-3-yl)methanol(48b) (3.456 g, 13.92 mmol) in anhydrous methanol (120 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.827 g, 3.48 mmol)followed by sodium borohydride (1.054 g, 27.8 mmol) was in smallportions over a period of 5 min. The reaction was exothermic andeffervescent. The reaction mixture was stirred for 20 min at 0° C. TLCanalysis (ethyl acetate/hexanes, 2/8, v/v) shows reaction was completeat this point N1-(2-aminoethyl)ethane-1,2-diamine (15.04 mL, 139 mmol)was added. The mixture was allowed to stir for 30 minutes andconcentrated in vacuum to dryness. The residue was treated water (75mL), and extracted with ethyl acetate (2×75 mL). Organic layer werecombined dried over anhydrous MgSO₄, filtered, and excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography [(silica gel 80 g, eluting with ethylacetate/hexanes from 0 to 50%)] to furnish(3-amino-4-fluorophenyl)(pyridin-3-yl)methanol (48c) (1.889 g, 62%yield) as a orange yellow oil.

¹H NMR (300 MHz, DMSO-d₆) δ 8.59-8.50 (m, 1H), 8.42 (dd, J=4.8, 1.7 Hz,1H), 7.74-7.58 (m, 1H), 7.32 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 6.90 (dd,J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=8.9, 2.2 Hz, 1H), 6.52 (ddd, J=8.3,4.5, 2.2 Hz, 1H), 5.97 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.61 (d,J=3.9 Hz, 1H), 5.11 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −137.43; MS (ES⁺): MS (ES+) 219.1 (M+1), 241.1 (M+Na), MS(ES+) 217.1 (M−1).

Step-3: Preparation of1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48d)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.88 g, 10.23 mmol), (3-amino-4-fluorophenyl)(pyridin-3-yl)methanol(48c) (1.861 g, 8.53 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (4.77 g, 10.23 mmol) was addedN,N-dimethylformamide (DMF) (52 mL) andN-ethyl-N-isopropylpropan-2-amine (DIPEA) (7.43 mL, 42.6 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder a positive flow of nitrogen atmosphere. Excess DMF was pumped-offunder reduced pressure. The residue was treated with water (50 mL), andextracted with ethyl acetate (2×50 mL). Combined organic layers weredried over anhydrous MgSO₄, filtered, evaporated to dryness. The residuewas purified by flash column chromatography [silica gel 40 g, elutingwith methanol in chloroform from 0-80%] to furnish1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48d) (2.707 g, 5.62 mmol, 66% yield) as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.56 (s, 1H, D₂O exchangeable), 8.58 (d, J=2.2 Hz,1H), 8.43 (dd, J=4.8, 1.7 Hz, 1H), 8.17-8.09 (m, 1H), 8.00 (dt, J=7.8,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 7.77-7.68 (m, 3H), 7.56(dd, J=7.5, 2.0 Hz, 1H), 7.38-7.20 (m, 3H), 6.20 (d, J=4.0 Hz, 1H, D₂Oexchangeable), 5.79 (d, J=4.0 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.98, −122.90; IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CN stretching); MS (ES⁺):MS (ES+) 482.2 (M+1), MS (ES−) 480.2 (M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48e)

To a solution of1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48d) (0.784 g, 1.629 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.356 mL, 4.89 mmol), reaction mixture allowedto warm to room temperature and stirred for 12 h. The reaction mixturewas quenched with cyclopropylmethanol (0.585 mL, 8.14 mmol), addedacetonitrile (20 mL), stirred for 1 h at room temperature andconcentrated in vacuum to dryness. The residue was dissolved incyclopropylmethanol (5.97 mL, 81 mmol) added acetonitrile (20 mL),triethylamine (0.681 mL, 4.89 mmol) and heated at 100° C. for 24 h. Thereaction mixture was cooled to room temperature and evaporated todryness. The residue was purified by flash column chromatography (silicagel 40 g, eluting with methanol in chloroform from 0-100%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48e) (378 mg, 43% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O exchangeable), 8.58 (d,J=2.1 Hz, 1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H), 8.17-8.10 (m, 1H), 8.00(dt, J=7.7, 1.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.78-7.67 (m, 3H), 7.62-7.54(m, 1H), 7.43-7.25 (m, 3H), 5.59 (s, 1H), 3.25 (d, J=6.8 Hz, 2H), 1.05(dddd, J=14.8, 6.8, 5.0, 2.6 Hz, 1H), 0.53-0.39 (m, 2H), 0.15 (dtd,J=5.5, 3.7, 3.3, 1.5 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.99,−122.10; MS (ES⁺): MS (ES+) 536.2 (M+1), MS (ES−) 534.2 (M−1).

Step-5: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48f)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48e) (0.238 g, 0.444 mmol) in anhydrous methanol (30 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.158 g, 0.667 mmol),sodium borohydride (0.135 g, 3.56 mmol) was added in small portions overa period of 5 min. The reaction was stirred for 25 min quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.480 mL, 4.44 mmol), stirred for30 mins and concentrated in vacuum. The reaction mixture was treatedwith saturated aqueous NH₄Cl (60 mL), and product was extracted withchloroform (2×60 mL). The combined organic layers were dried over MgSO₄,filtered and evaporated to dryness. The residue was purified by flashcolumn chromatography [(silica gel 25 g, eluting withmethanol/chloroform from 0 to 50%)] to furnish Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48f) (0.129 g, 0.239 mmol, 53.8% yield) as white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.57 (d, J=2.2 Hz, 1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H),7.71 (dt, J=8.0, 2.0 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.58 (s, 1H), 7.52(s, 1H), 7.47-7.41 (m, 2H), 7.40-7.25 (m, 4H), 5.59 (s, 1H), 3.77 (s,2H), 3.25 (d, J=6.8 Hz, 2H), 1.15-0.96 (m, 1H), 0.56-0.35 (m, 2H),0.23-0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −122.56; MS(ES⁺): MS (ES+) 540.2 (M+1), MS (ES−) 538.2 (M−1), 574.1 (M+Cl);Analysis calculated for C₂₈H₂₅F₄N₅O₂.0.25H₂O: C, 61.82; H, 4.72; N,12.87; Found: C, 61.89; H, 4.91; N, 12.75.

Step-6: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48g) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48h)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48f) (725 mgs) was separated using chiral preparative HPLC usingCHIRALPAK IC, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 80%Hexane/20% EtOH/0.1% DEA, UV=320 nM, 25° C., to furnish:

-   -   1.        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48g) (358.5 mg as peak-1, R_(t)=6.758 min, 99.2473% for peak-1        (compound 48g), R_(t)=9.193 min, 0.7527% for peak-2 (compound        48h), 97.1% ee for 48g. This was repurified by flash column        chromatography (silica gel 25 g, eluting methanol in chloroform        for 25 mins) to afford pure        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48g) (180 mg) as a white solid; The free base of pure        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48g) was dissolved in methanol and added (4 mL) of 2 N HCl in        methanol. The mixture was concentrated in vacuum to dryness to        furnish pure        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48g) (180 mg) as dihydrochloride salt; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.78 (s, 1H, D₂O exchangeable), 8.86 (d, J=2.0 Hz,        1H), 8.78 (dd, J=5.5, 1.5 Hz, 1H), 8.53 (s, 3H, D₂O        exchangeable), 8.37-8.28 (m, 1H), 7.89 (dd, J=8.1, 5.4 Hz, 1H),        7.77-7.61 (m, 4H), 7.59-7.47 (m, 2H), 7.40-7.25 (m, 2H), 5.80        (s, 1H), 4.11 (q, J=5.9 Hz, 2H), 3.31 (s, 2H), 1.06 (ddt, J=9.3,        7.5, 2.8 Hz, 1H), 0.56-0.33 (m, 2H), 0.26-0.09 (m, 2H); MS (ES+)        541.3 (M+1), (ES−) 538.3 (M−1), 574.3 (M+35); Optical Rotation        [c]D=+10.228 [CH₃OH, 1.095]; Chiral purity checked by performing        chiral HPLC using chiral AD-H column, 0.8 mL/min, Solvent: 85%        Hexane/15% EtOH/0.1% TEA, UV=260 nM, 40° C.; C (Rt=8.860 min,        99.1567% for peak-1 compound 48g), (Rt=14.127, 0.8433% for        peak-2, compound 48h) (98.31% ee for 48g HCl salt); Analysis        calculated for C₂₈H₂₅F₄N₅O₂.2.05HCl.1.75H₂O: C, 52.08; H, 4.77;        Cl, 11.25; N, 10.84; Found: C, 52.07; H, 4.80; Cl, 11.46; N,        10.60    -   2.        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48h) (382.5 mg as peak-2, R_(t)=6.861 min, 3.7692% for peak-1        (compound 48g) R_(t)=9.131 min, 96.2308% for-peak 2 (compound        48h), 92.4% ee for compound 48h. This was repurified by flash        column chromatography (silica gel 12 g, eluting 0-30% MeOH in        chloroform for 25 mins) to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48h) (0.255 g) as a white solid. The free base of pure        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48h) (245 mg) was dissolved in methanol (8 mL) and added 2 N        HCl (in methanol, 2.25 mL, 10 eq). The solution was and stirred        at room temperature for 30 min, evaporated to dryness to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (48h) (238 mg) hydrochloride salt as an yellow solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.76 (s, 1H, D₂O exchangeable), 8.83 (d,        J=2.0 Hz, 1H), 8.75 (dd, J=5.4, 1.5 Hz, 1H), 8.49 (bs, 3H, D₂O        exchangeable), 8.27 (d, J=8.1 Hz, 1H), 7.85 (dd, J=8.1, 5.4 Hz,        1H), 7.76-7.60 (m, 4H), 7.59-7.48 (m, 2H), 7.40-7.25 (m, 2H),        5.78 (s, 1H), 4.11 (q, J=5.8 Hz, 2H), 3.29 (d, J=6.8 Hz, 2H),        1.17-0.97 (m, 1H), 0.59-0.37 (m, 2H), 0.25-0.11 (m, 2H); ¹H NMR        (300 MHz, DMSO d6, D₂O) δ 8.81 (d, J=2.0 Hz, 1H), 8.71 (dd,        J=5.5, 1.5 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 5.5        Hz, 1H), 7.70 (s, 1H), 7.67 (d, J=7.0 Hz, 1H), 7.63 (s, 1H),        7.60 (d, J=2.1 Hz, 1H), 7.57 (s, 1H), 7.52 (td, J=4.9, 2.5 Hz,        1H), 7.41-7.28 (m, 2H), 5.76 (s, 1H), 4.12 (s, 2H), 3.30 (dd,        J=6.9, 2.0 Hz, 2H), 1.05 (dq, J=8.6, 5.2, 4.3 Hz, 1H), 0.57-0.40        (m, 2H), 0.26-0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80        (d, J=2.5 Hz), −121.44; MS (ES+) 540.3 (M+1), MS (ES−) 538.3        (M−1), 574.2 (M+Cl); Optical Rotation [α]_(D)=−9.16 [CH₃OH,        0.83].

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49h),(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49i) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49j) Step-1: Preparation of 2-(benzyloxy)benzaldehyde (49b)

To a solution of 2-hydroxybenzaldehyde (49a) (3.98 mL, 38 mmol) in DMF(12 mL) was added cesium carbonate (15.48 g, 47.5 mmol) and benzylbromide (4.97 mL, 41.8 mmol). The reaction mixture was stirred at roomtemperature for 36 h and quenched with cold water (50 mL). The solidobtained was collected by filtration washed with water (2×50 mL) anddried under reduced pressure over P205 to furnish2-(benzyloxy)benzaldehyde (49b)(6.524 g, 81%) as white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.43 (d, J=0.8 Hz, 1H), 7.75-7.62 (m, 2H),7.56-7.49 (m, 2H), 7.46-7.30 (m, 4H), 7.10 (tt, J=7.5, 0.9 Hz, 1H), 5.30(s, 2H); MS (ES⁺): MS (ES+) 235.2 (M+Na).

Step-2: Preparation of (3-aminophenyl)(2-(benzyloxy)phenyl)methanol(49d)

To a solution of 2-(benzyloxy)benzaldehyde (3 g, 14.13 mmol) intetrahydrofuran (10 mL) was added 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride solution (49c) (16.96 mL, 16.96mmol, 1 M solution in THF) at 0° C. The reaction was stirred for 14 h atroom temperature and quenched at 0° C. with hydrogen chloride (17.67 mL,35.3 mmol), stirred for 6 h. The reaction mixture was treated withsodium hydroxide (21.20 mL, 42.4 mmol) and extracted with ethyl acetate(2×75 mL). The organic layers were combined washed with saturatedaqueous NH₄Cl (75 mL), dried over anhydrous MgSO₄, filtered, evaporatedto dryness. The crude residue was purified by flash columnchromatography (silica gel 80 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-aminophenyl)(2-(benzyloxy)phenyl)methanol (49d)(4.02 g, 93%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.47 (dd,J=7.5, 1.8 Hz, 1H), 7.41-7.28 (m, 5H), 7.16 (ddd, J=8.9, 7.3, 1.8 Hz,1H), 7.03-6.82 (m, 3H), 6.56 (t, J=1.9 Hz, 1H), 6.46 (dt, J=7.6, 1.3 Hz,1H), 6.37 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.90 (d, J=4.3 Hz, 1H), 5.48(d, J=4.3 Hz, 1H, D₂O exchangeable), 5.09 (s, 2H), 4.93 (s, 2H, D₂Oexchangeable); MS (ES+): MS (ES+) 328.3 (M+Na), MS (ES−) 304.16 (M−1).

Step-3: Preparation ofN-(3-((2-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49e)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.381 g, 4.91 mmol), (3-aminophenyl)(2-(benzyloxy)phenyl)methanol (49d)(1.5 g, 4.91 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (2.75 g, 5.89 mmol) was addedN,N-dimethylformamide (28.5 mL, 368 mmol) andN-ethyl-N-isopropylpropan-2-amine (4.28 mL, 24.56 mmol) successively ina positive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. Excess DMF was pumped-off under reducedpressure. The residue was treated with water (50 mL), and extracted withchloroform (2×50 mL). The combined organics layers were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue was thenpurified by flash column chromatography [silica gel 40 g, eluting withethyl acetate in hexanes from 0-100%] to furnishN-(3-((2-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49e) (2.568 g, 92% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.62 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H), 7.99 (dt,J=7.8, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.76-7.68 (m,2H), 7.64 (t, J=1.8 Hz, 1H), 7.50 (ddd, J=9.6, 8.1, 1.8 Hz, 2H),7.34-7.29 (m, 4H), 7.25-7.15 (m, 2H), 7.09-6.91 (m, 4H), 6.01 (d, J=4.2Hz, 1H), 5.76 (d, J=4.2 Hz, 1H, D₂O exchangeable), 5.09 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.95; IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CN stretching);MS (ES⁺): MS (ES+) 591.2 (M+Na), MS (ES−) 567.2 (M−1).

Step-4: Preparation ofN-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49f)

To a solution ofN-(3-((2-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49e) (2.491 g, 4.38 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.959 mL, 13.14 mmol) and allowed to warm to roomtemperature, after 13 h additional thionyl chloride (0.959 mL, 13.14mmol) was added and stirred for 1.5 h. The reaction mixture was quenchedwith cyclopropylmethanamine (2.63 mL, 30.7 mmol) stirred for 1 h at roomtemperature, and concentrated in vacuum to dryness. The residue wasdissolved in cyclopropylmethanamine (7.51 mL, 88 mmol) and acetonitrile(20 mL) and heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuum and residue obtained was treated with water (50mL), extracted with ethyl acetate (2×50 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered and excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-100% ethyl acetate inhexanes from 0-100%) to affordN-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49f) (1.168 g, 43% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.61 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H), 7.99 (dt,J=7.7, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 7.76-7.64 (m,3H), 7.53 (dd, J=8.3, 1.9 Hz, 1H), 7.44 (dd, J=7.6, 1.7 Hz, 1H),7.41-7.27 (m, 5H), 7.26-7.07 (m, 3H), 7.01 (dd, J=8.2, 1.1 Hz, 1H), 6.93(td, J=7.4, 1.1 Hz, 1H), 5.21 (s, 1H), 5.08 (s, 2H), 2.30 (d, J=7.6 Hz,1H), 2.24 (s, 1H), 2.22 (s, 1H), 0.88 (q, J=6.7 Hz, 1H), 0.41-0.29 (m,2H), 0.02-−0.01 (m, 2H); MS (ES⁺): MS (ES+) 622.3 (M+1), MS (ES−) 620.3(M−1).

Step-5: Preparation of tert-butyl3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(49g)

To a stirred solution ofN-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49f) (1.11 g, 1.786 mmol) in anhydrous methanol (20 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.531 g, 2.232 mmol),sodium borohydride (0.540 g, 14.28 mmol) was then added in smallportions over 5 min. The reaction mixture was stirred for 45 min at 0°C., quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.929 mL, 17.86mmol), stirred for additional 30 minutes and concentrated in vacuum.

The residue was treated with water (50 mL) and extracted with chloroform(2×50 mL). The organic layers were combined dried over anhydrous MgSO₄,filtered, excess solvents were pumped-off under reduced pressure. Theresidue was purified by flash column chromatography [(silica gel 40 g,eluting with methanol/chloroform from 0 to 100%)] to furnish tert-butyl3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(49g) (525 mg, 40% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H, D₂O exchangeable), 7.62 (s, 2H), 7.58-7.28 (m, 12H), 7.07(dd, J=50.3, 30.3 Hz, 4H), 5.21 (s, 1H), 5.09 (s, 2H), 4.18 (d, J=6.2Hz, 2H), 2.25 (d, J=15.2 Hz, 3H), 1.36 (s, 9H), 0.87 (s, 1H), 0.34 (s,2H), −0.00 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES⁺): MS(ES+) 726.5 (M+1), MS (ES−) 724.4 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49h)

To a solution of tert-butyl3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(49g) (0.496 g, 0.683 mmol) in methanol (30 mL) was added hydrogenchloride (4N in dioxane) (4.27 mL, 17.08 mmol) and palladium (10% Pd oncarbon) (0.218 g, 0.205 mmol). The reaction mixture was hydrogenated at60 psi for 14 h at room temperature. The reaction mixture was filteredthrough a small Celite pad, Celite pad was subsequently washed withmethanol (2×25 mL), and ethyl acetate (25 mL). Excess solvents werepumped-off under reduced pressure. The residue was dissolved inisopropanol (15 mL), then the solution was treated with ethyl ether (30mL), refluxed for 1 h, cooled to room temperature. The solid obtainedwas collected by filtration. Solid was dissolved in methanol, filteredthrough a syringe filter, and pumped-off the excess solvent, this cyclewas repeated thrice, after these steps, compound was dried under reducedpressure to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49h) (211 mg, 58% yield) as an off-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.36 (s, 1H, D₂Oexchangeable), 10.02 (s, 1H, D₂O exchangeable), 9.76 (s, 1H, D₂Oexchangeable), 8.56 (s, 3H, D₂O exchangeable), 7.83 (t, J=1.7 Hz, 1H),7.77-7.69 (m, 3H), 7.68-7.47 (m, 5H), 7.40 (t, J=7.9 Hz, 1H), 7.23-7.12(m, 1H), 6.97 (dd, J=8.3, 1.2 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 5.83-5.65(m, 1H), 4.11 (q, J=5.7, 5.2 Hz, 2H), 2.83-2.64 (m, 2H), 1.22-1.07 (m,1H), 0.54 (dt, J=7.9, 3.0 Hz, 2H), 0.31 (t, J=5.0 Hz, 2H); ¹H NMR (300MHz, DMSO-d₆, D₂O) δ 10.96 (s, 1H), 7.80 (s, 1H), 7.72 (t, J=1.8 Hz,1H), 7.69-7.38 (m, 8H), 7.27-7.17 (m, 1H), 6.99-6.86 (m, 2H), 5.71 (s,1H), 4.13 (s, 2H), 2.75 (d, J=7.3 Hz, 2H), 1.09 (tt, J=8.1, 4.8 Hz, 1H),0.69-0.45 (m, 2H), 0.40-0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.75; MS (ES⁺): MS (ES+) 536.3 (M+1), 534.3 (M−1), 570.3 (M+Cl);Analysis calculated for: C₂₉H₂₈F₃N₅O₂.6H₂O.2.75HCl: C, 46.82; H, 5.79;Cl, 13.11; N, 9.41; Found: C, 47.02; H, 5.49; Cl, 12.78; N, 9.37.

Step-7: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49i) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49j)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(49h) (1.09 g) was separated using chiral preparative HPLC usingCHIRALPAK AY-H, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 90% ACN/10%MeOH/0.1% DEA, UV=320 nM, to furnish:

-   -   1.        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49i) (0.5415 g, >99% ee) Rt=4.672 min (100%) (as peak-1, for        49i) Rt=5.448 (0% peak-2, for 49j). This product was repurified        by flash column chromatography (silica gel 25 g, eluting 0-25%        methanol in chloroform for 13 mins) to furnish pure        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49i) (0.31 g) as a white solid. Optical rotation +52.03 (MeOH,        1.18); ¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 10.73 (s, 1H),        7.67-7.61 (m, 1H), 7.59-7.50 (m, 3H), 7.46-7.40 (m, 2H), 7.31        (dq, J=4.9, 2.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (dt,        J=7.9, 1.4 Hz, 1H), 7.02 (dtd, J=7.4, 4.5, 4.0, 1.7 Hz, 2H),        6.73-6.64 (m, 2H), 5.00 (s, 1H), 3.77 (s, 2H), 2.47-2.37 (m,        1H), 2.33-2.21 (m, 1H), 1.00-0.90 (m, 1H), 0.40 (dt, J=9.0, 2.9        Hz, 2H), 0.17-0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.68; MS        (ES+) 536.3 (M+1); (ES−) 534.3 (M−1). The free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49i) was dissolved in methanol and added (2.5 mL) of 2 N HCl in        methanol. The mixture was concentrated in vacuum to dryness to        furnish        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49i) (300 mgs) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ 10.94        (s, 1H), 10.32 (s, 1H), 9.88 (d, J=11.6 Hz, 1H), 9.63 (s, 1H),        8.44 (s, 3H), 7.81 (s, 1H), 7.72 (t, J=1.7 Hz, 1H), 7.70-7.59        (m, 4H), 7.59-7.48 (m, 3H), 7.41 (t, J=7.9 Hz, 1H), 7.24-7.14        (m, 1H), 6.97-6.84 (m, 2H), 5.72 (d, J=6.6 Hz, 1H), 4.12 (q,        J=5.8, 5.4 Hz, 2H), 2.73 (d, J=6.4 Hz, 2H), 1.19-1.01 (m, 1H),        0.65-0.46 (m, 2H), 0.38-0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ        −60.75; MS (ES+) 536.3 (M+1); (ES−) 570.3 (M+Cl); Analysis        calculated for C₂₉H₂₈F₃N₅O₂.2HCl.1.25H₂O: C, 55.20; H, 5.19; Cl,        11.24; N, 11.10; Found: C, 55.37; H, 5.20; Cl, 10.80; N, 10.61.    -   2.        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49j) (0.670 g, 76.341% ee) Rt=4.668 min (11.8295%) (peak-1, for        49i) Rt=5.447 (88.1705% peak-2, for 49j). This product was        repurified by flash column chromatography (silica gel 25 g,        eluting 0-30% methanol in chloroform for 30 mins) to furnish        pure        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49j) (0.461 g) as a yellow waxy solid. Optical rotation −40.85        (MeOH, 2.11); ¹H NMR (300 MHz, DMSO-d₆) δ 10.73 (s, 1H, D₂O        exchangeable), 7.65 (d, J=2.2 Hz, 1H), 7.56 (q, J=2.7, 1.6 Hz,        2H), 7.52 (s, 1H), 7.47-7.41 (m, 2H), 7.33-7.27 (m, 3H), 7.22        (dd, J=10.0, 8.5 Hz, 1H), 7.03 (ddd, J=7.1, 4.2, 2.4 Hz, 2H),        6.72-6.65 (m, 2H), 5.00 (s, 1H), 3.78 (s, 2H), 2.46-2.39 (m,        1H), 2.26 (dd, J=12.3, 7.0 Hz, 1H), 0.94 (d, J=7.3 Hz, 1H), 0.40        (dt, J=8.7, 2.8 Hz, 2H), 0.17-0.03 (m, 2H); 1H NMR (300 MHz,        DMSO-d₆ D₂O) δ 7.65 (d, J=2.0 Hz, 1H), 7.60-7.50 (m, 2H),        7.45-7.41 (m, 2H), 7.36-7.27 (m, 3H), 7.26-7.17 (m, 1H), 7.03        (t, J=7.5 Hz, 2H), 6.71 (d, J=1.5 Hz, 1H), 6.70-6.68 (m, 1H),        5.00 (s, 1H), 3.76 (s, 2H), 2.45-2.38 (m, 1H), 2.25 (dd, J=12.2,        7.0 Hz, 1H), 0.96 (dd, J=14.1, 7.1 Hz, 1H), 0.51-0.29 (m, 2H),        0.08 (dt, J=5.3, 2.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.70; MS (ES+) 536.3 (M+1), 534.3 (M−1). The free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49j) (0.451 g) was dissolved in methanol (15 mL) and added        (4.21 mL of 2 N HCl in methanol, 10 equi). The mixture was        concentrated in vacuum to dryness to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (49j) (386 mg) HCl salt as an off-white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.96 (s, 1H), 10.35 (s, 1H), 9.95 (s, 1H), 9.70 (s,        1H), 8.50 (s, 3H), 7.82 (t, J=1.8 Hz, 1H), 7.75-7.67 (m, 3H),        7.64 (dt, J=7.7, 1.8 Hz, 2H), 7.60-7.48 (m, 3H), 7.45-7.26 (m,        4H), 7.18 (ddd, J=8.6, 7.3, 1.6 Hz, 1H), 6.96 (dd, J=8.2, 1.2        Hz, 1H), 6.93-6.83 (m, 1H), 6.73 (s, 2H), 6.10 (s, 6H), 5.72 (t,        J=6.6 Hz, 1H), 4.12 (d, J=5.8 Hz, 2H), 2.73 (d, J=6.1 Hz, 2H),        1.12 (s, 1H), 0.67-0.47 (m, 2H), 0.30 (h, J=4.0 Hz, 2H); 1H NMR        (300 MHz, DMSO-d₆, D₂O) δ 10.95 (s, 1H), 7.79 (s, 1H), 7.71 (t,        J=1.8 Hz, 1H), 7.63 (d, J=4.8 Hz, 2H), 7.60 (dd, J=3.7, 2.0 Hz,        1H), 7.56 (td, J=4.5, 2.1 Hz, 2H), 7.52 (t, J=2.0 Hz, 1H),        7.50-7.43 (m, 3H), 7.22 (ddd, J=8.6, 7.3, 1.6 Hz, 1H), 7.01-6.85        (m, 2H), 5.71 (s, 1H), 4.13 (s, 2H), 2.75 (d, J=7.2 Hz, 2H),        1.18-0.99 (m, 1H), 0.71-0.47 (m, 2H), 0.40-0.16 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.76; MS (ES+) 536.3 (M+1), 534.3 (M−1),        570.3 (M+Cl).

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50f);(+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50g) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50h) Step-1: Preparation of (3-aminophenyl)(4-nitrophenyl)methanol(50b)

To a solution of 4-nitrobenzaldehyde (50a) (5 g, 32.4 mmol) intetrahydrofuran (60 mL) was added3-[bis(trimethylsilyl)amino]phenylmagnesium chloride solution (49c)(36.0 g, 36 mmol) at 0° C. The reaction was stirred for 2 h at at 0° C.room and quenched with saturated aqueous NH₄Cl (100 mL). The reactionmixture was extracted with ethyl acetate (2×120 mL).

The organic layers were combined washed with brine (100 mL), dried overanhydrous MgSO₄, filtered and evaporated to dryness. The crude residuewas purified by flash column chromatography [silica gel 120 g, elutingwith chloroform/CMA80 (1:0 to 2:1)] to give(3-aminophenyl)(4-nitrophenyl)methanol (50b) (3.524 g, 45%) as a darkbrown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.22-8.14 (m, 2H), 7.68-7.57 (m,2H), 6.94 (t, J=7.7 Hz, 1H), 6.59-6.49 (m, 2H), 6.40 (ddd, J=8.0, 2.3,1.0 Hz, 1H), 6.06 (d, J=3.8 Hz, 1H), 5.65 (d, J=3.8 Hz, 1H), 5.05 (s,2H); MS (ES+) 245.2 (M+1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50c)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.381 g, 4.91 mmol), (3-aminophenyl)(4-nitrophenyl)methanol (50b) (1.19g, 4.91 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (6.65 g, 13.98 mmol) was addedN,N-dimethylformamide (80 mL) and N-ethyl-N-isopropylpropan-2-amine(20.00 mL, 115 mmol) successively in a positive flow of nitrogen at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 14 h under a positive flow of nitrogen atmosphere. Thereaction mixture was diluted with ethyl acetate (300 mL), washed withwater (2×120 mL), brine (120 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel 120 g, eluting with hexanes/ethyl acetate(1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50c) (3.8 g, 54%) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.23-8.14 (m, 3H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90(ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78-7.61 (m, 5H), 7.57 (dt, J=8.1, 1.4Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.21-7.15 (m, 1H), 6.31 (d, J=3.9 Hz,1H), 5.85 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS(ES+) 530.3 (M+23).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-nitrophenyl)-methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50c) (1.9 g, 3.74 mmol) in dichloromethane (60 mL) at 0° C. was addedthionyl chloride (0.790 mL, 10.67 mmol) and warmed to room temperatureover 2 h. The reaction mixture was quenched with triethyl amine (4.60mL, 33.0 mmol) stirred at room temperature for 1 h. It was then treatedwith cyclopropylmethanamine (5.49 g, 74.9 mmol), concentrated to removemost of dichloromethane followed by addition of acetonitrile (45 mL),stirring at 70° C. for 19 h, and concentration in vacuum to dryness. Theresidue was treated with chloroform (200 mL), washed with water (100mL), dried over MgSO₄ followed by filtration and concentration. Thecrude product was purified by flash column chromatography [silica geleluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-nitrophenyl)-methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50d) (466 mg) as a brown gum, which was pure enough to be taken to nextstep; MS (ES+) 561.3 (M+1).

Step-4: Preparation of tert-butyl 3-(5-((3-((4-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(50e)

To a stirred solution of afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-nitrophenyl)-methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50d) (458 mg, 0.817 mmol) in anhydrous methanol (12 mL), cooled to 0°C., were added di-tert-butyl dicarbonate (540 mg, 2.451 mmol) andnickel(II) chloride hexahydrate (105 mg, 0.442 mmol) and sodiumborohydride (0.540 g, 14.28 mmol) was then added in small portions over5 min. The reaction mixture was stirred for 45 min at 0° C., quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.410 mL, 3.75 mmol), stirredfor additional 30 minutes and concentrated in vacuum. The residue wastreated with ethyl acetate (120 mL) washed with water (60 mL). theaqueous layer was extracted again with ethyl acetate (80 mL). Theorganic layers were combined, washed with brine (80 mL) dried overanhydrous MgSO₄, filtered and concentrated in vacuum. The residue waspurified by flash column chromatography [silica gel 40 g, eluting withhexanes/ethyl acetate (1:0 to 1:1)] to afford tert-butyl3-(5-((3-((4-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(50e) (81 mg, 3% for 2 steps) as a white solid, MS (ES+) 735.5 (M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50f)

To a solution of tert-butyl 3-(5-((3-((4-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(50e) (79 mg, 0.108 mmol) in 1,4-Dioxane (8 mL) was added dropwisehydrogen chloride (1.2 mL, 4.8 mmol, 4 M in 1,4-dioxane) and stirred atroom temperature for 15 h. The reaction mixture was diluted withhexanes, decanted, washed with hexanes, and decanted again. Theinsoluble crude product was purified by flash column chromatography[silica gel, eluting with chloroform/CMA80 (1:0 to 2:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50f) (41 mg) as a light yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65(s, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.56 (s, 1H), 7.54-7.46 (m, 2H),7.46-7.38 (m, 2H), 7.31 (dt, J=6.5, 2.5 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H),7.16-7.10 (m, 1H), 7.03-6.96 (m, 2H), 6.51-6.41 (m, 2H), 4.90 (s, 2H),4.61 (s, 1H), 2.26 (d, J=6.7 Hz, 2H), 2.05 (s, 2H), 0.90 (p, J=7.0 Hz,1H), 0.44-0.22 (m, 2H), 0.09-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.70; MS (ES+) 535.3 (M+1), (ES−) 533.3 (M−1); IR (KBr pellet, cm⁻¹):3441, 3005, 1616, 1558, 1243; Analysis calculated forC₂₉H₂₉F₃N₆O.1.0H₂O: C, 63.03; H, 5.65; N, 15.21; Found: C, 63.42; H,5.41; N, 14.83.

Step-6: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50g) and(−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50h)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50f) (0.201 g) was separated using chiral preparative HPLC usingCHIRALPAK IC column, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 70%Hexane/30% EtOH/0.1% DEA, UV=254 nM, to furnish:

-   -   1.        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50g) (0.091 g, Rt=7.73 min (100%), >99.9% ee), Optical rotation        +10.37 (MeOH, 0.54); ¹H NMR (300 MHz, Methanol-d₄) δ 7.55-7.50        (m, 2H), 7.48-7.42 (m, 3H), 7.45-7.34 (m, 1H), 7.32 (s, 1H),        7.26 (t, J=7.8 Hz, 1H), 7.18 (dt, J=7.7, 1.4 Hz, 1H), 7.13-7.06        (m, 2H), 6.70-6.62 (m, 2H), 4.75 (s, 1H), 3.83 (s, 2H), 2.36 (d,        J=6.9 Hz, 2H), 1.03-0.88 (m, 1H), 0.52-0.40 (m, 2H), 0.06 (qd,        J=4.5, 2.9 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H),        7.60 (t, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.54-7.40 (m, 4H), 7.31        (dt, J=6.2, 2.4 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.16-7.10 (m,        1H), 7.04-6.95 (m, 2H), 6.49-6.42 (m, 2H), 4.91 (s, 2H), 4.61        (s, 1H), 3.78 (s, 2H), 2.26 (d, J=6.7 Hz, 2H), 0.97-0.84 (m,        1H), 0.40-0.31 (m, 2H), 0.09-−0.02 (m, 2H); ¹⁹F NMR (282 MHz,        MeOD) δ −63.72; ¹⁹F NMR (282 MHz, DMSO) δ −60.71; MS (ES+) 557.3        (M+Na); (ES−) 533.3 (M−1). The free base        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50g) (0.085 g, 0.159 mmol) was dissolved in methanol (5 mL) and        added HCl (0.133 mL, 1.590 mmol). The reaction mixture was        concentrated in vacuum to dryness and co-distilled twice with        chloroform dried in vacuum to furnish        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50g) (0.07 g, 0.109 mmol) trihydrochloride as a yellow solid;        ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.08 (s, 2H), 8.50        (s, 3H), 7.91-7.81 (m, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.71 (s,        1H), 7.66-7.57 (m, 5H), 7.56-7.49 (m, 2H), 7.44 (t, J=7.9 Hz,        1H), 7.15 (d, J=7.9 Hz, 2H), 5.54 (t, J=6.2 Hz, 1H), 4.12 (q,        J=5.8 Hz, 2H), 2.88-2.59 (m, 2H), 1.21-1.09 (m, 1H), 0.65-0.45        (m, 2H), 0.40-0.19 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78;        MS (ES+) 535.4 (M+1), 557.3 (M+Na); (ES−) 533.3 (M−1), 569.3        (M+Cl); Analysis calculated for C₂₉H₂₉F₃N₆O.3HCl.1.75H₂O: C,        51.56; H, 5.30; N, 12.44; Found; C, 51.68; H, 5.61; N, 11.54.    -   2.        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50h) (0.132 g, Rt=10.449 min (99.6604%), >99.4% ee); ¹H NMR        (300 MHz, Methanol-d₄) δ 7.72 (t, J=1.8 Hz, 1H), 7.66 (d, J=1.8        Hz, 1H), 7.55 (ddq, J=13.2, 6.1, 1.6 Hz, 4H), 7.44-7.34 (m, 2H),        7.28 (dt, J=7.9, 1.4 Hz, 1H), 7.21-7.13 (m, 2H), 6.75-6.60 (m,        2H), 5.14 (s, 1H), 4.14 (s, 2H), 2.65 (d, J=7.2 Hz, 2H),        1.12-0.98 (m, 1H), 0.67-0.52 (m, 2H), 0.27-0.14 (m, 2H); ¹⁹F NMR        (282 MHz, Methanol-d₄) δ −63.80; MS (ES+) 535.4 (M+1); 557.3        (M+Na); (ES−) 569.3 (M+Cl). This product was repurified by flash        column chromatography (silica gel 4 g, eluting with 0-100%        CMA-80 in chloroform) to furnish pure        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50h) (36 mgs) of free base as a white solid. Optical rotation        −11.5 (MeOH, 1.8); The above free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (50h) (0.036 g, 0.067 mmol) was dissolved in methanol (5 mL) and        added HCl (0.056 mL, 0.673 mmol).

The reaction mixture was concentrated in vacuum to dryness andco-distilled twice with chloroform dried in vacuum to furnish(−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(50h) (0.04 g) trihydrochloride as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.97 (s, 1H), 10.12-9.91 (m, 2H), 8.47 (s, 3H), 7.88-7.81(m, 1H), 7.74-7.71 (m, 1H), 7.70 (s, 1H), 7.66-7.48 (m, 7H), 7.44 (t,J=7.9 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 5.51 (d, J=6.6 Hz, 1H), 4.12 (q,J=5.7 Hz, 2H), 2.69 (q, J=6.4 Hz, 2H), 1.23-1.05 (m, 1H), 0.65-0.44 (m,2H), 0.39-0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78; MS (ES+)535.4 (M+1); 557.4 (M+Na); (ES−) 569.3 (M+Cl); Analysis calculated forC₂₉H₂₉F₃N₆O.3HCl.3H₂O: C, 49.90; H, 5.49; N, 12.04; Found: C, 49.85; H,5.49; N, 11.45.

Preparation of Racemic1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51f);(−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51g) and(+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51h) Step-1: Preparation of(3-Amino-phenyl)-(2-methoxy-naphthalen-1-yl)-methanol (51b)

To a stirred solution of 2-Methoxy-naphthalene-1-carbaldehyde (51a) (1.2g, 10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was nuetralized with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith brine (50 mL), dried over anhydrous MgSO₄, filtered andconcentrated in vacuum to dryness. The crude residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexane) to furnish(3-amino-phenyl)-(4-methoxy-naphthalen-1-yl)-methanol (51b) (1.7 g, 94%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.26-8.18 (m, 1H),7.86 (d, J=9.0 Hz, 1H), 7.81-7.74 (m, 1H), 7.48 (d, J=9.1 Hz, 1H),7.29-7.16 (m, 2H), 6.86 (t, J=7.7 Hz, 1H), 6.67-6.60 (m, 1H), 6.56 (dt,J=2.3, 1.2 Hz, 1H), 6.49 (dq, J=7.7, 1.1 Hz, 1H), 6.31 (ddt, J=7.8, 2.0,0.9 Hz, 1H), 5.82 (d, J=4.6 Hz, 1H), 4.90 (s, 2H), 3.96 (s, 3H); MS(ES+) 302.2 (M+Na), MS (ES−) 557.2 (2M−1).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid{3-[hydroxy-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide (51c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.71g, 6.085 mmol) in DMF (40 mL) was added(3-Amino-phenyl)-(2-methoxy-naphthalen-1-yl)-methanol (51b) (1.7 g,6.085 mmol), N-ethyl-N-isopropylpropan-2-amine (8.5 mL, 48.68 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 2.836 g,6.085 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 42 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (40 mL) washed with water (2×40 mL), brine(100 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography (silica gel 120 g,eluting with ethyl acetate in hexanes from 0-30%) to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide (51c) (1.8g, 54.5% yield) as a pale sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H), 8.21-8.11 (m, 2H), 7.99 (dt, J=7.8, 1.3 Hz, 1H),7.93-7.86 (m, 2H), 7.83-7.77 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.69 (s,1H), 7.65-7.60 (m, 1H), 7.53 (dd, J=11.8, 8.1 Hz, 2H), 7.29-7.17 (m,3H), 7.11-7.04 (m, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.10 (d, J=4.6 Hz, 1H),3.98 (s, 3H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide(51d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide (51c) (1.8g, 3.317 mmol) in dichloromethane (50 mL) at 0° C. was added thionylchloride (0.74 g, 6.635 mmol) and stirred at room temperature for 4 h.The reaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (3.54 g, 49.77 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide(51d) (1.05 g, 53%) as pale liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70(s, 1H), 8.44-8.36 (m, 1H), 8.24 (t, J=1.8 Hz, 1H), 8.09 (dt, J=7.7, 1.4Hz, 1H), 7.96 (dd, J=11.7, 8.1 Hz, 3H), 7.83 (d, J=7.9 Hz, 1H), 7.76 (d,J=7.4 Hz, 2H), 7.63 (d, J=8.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.52-7.34(m, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 5.99 (s, 1H),3.96 (s, 3H), 2.72-2.62 (m, 2H), 2.29-2.13 (m, 1H), 1.11-0.85 (m, 1H),0.51-0.37 (m, 2H), 0.20-0.06 (m, 1H), 0.05-−0.07 (m, 1H).

Step-4: Preparation of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(2-methoxynaphthalen-1-yl)methyl)(cyclopropylmethyl)carbamate(51e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide(51d) (1.0 g, 1.678 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.48 g, 2.01 mmol) and Bocanhydride (1.1 g, 5.036 mmol) followed by portionwise addition of SodiumBorohydride (0.38 g, 10.073 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.5 mL, 4.197 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(2-methoxynaphthalen-1-yl)methyl)(cyclopropylmethyl)carbamate(51e) (0.8 g, 68.13%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H), 7.99 (d, J=9.1 Hz, 1H), 7.96-7.89 (m, 2H), 7.62-7.54 (m,1H), 7.55-7.40 (m, 3H), 7.43-7.37 (m, 3H), 7.35-7.24 (m, 4H), 7.15 (s,1H), 6.91-6.81 (m, 1H), 4.17 (d, J=6.2 Hz, 2H), 3.42 (s, 3H), 3.07 (dd,J=14.6, 6.8 Hz, 1H), 1.38 (d, J=5.3 Hz, 18H), 0.34 (p, J=6.7 Hz, 1H),0.00 (td, J=8.8, 4.5 Hz, 1H), −0.08-−0.25 (m, 1H), −0.21-−0.39 (m, 1H),−0.65-−0.87 (m, 1H).

Step-5: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51f)

To a solution of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(2-methoxynaphthalen-1-yl)methyl)(cyclopropylmethyl)carbamate(51e) (0.8 g, 1.143 mmol) in methanol (16 mL) was added conc. HCl (0.5mL). The reaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. The product were purified by flash columnchromatography (silica gel 12 g, eluting with 0-15% methanol inDichloromethane) to obtain free base of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51f) (170 mg, 24.8%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.82 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.90 (d,J=8.1 Hz, 1H), 7.82-7.68 (m, 2H), 7.66-7.43 (m, 6H), 7.42-7.24 (m, 3H),6.12 (s, 1H), 4.11 (s, 2H), 3.95 (s, 3H), 2.78-2.70 (m, 1H), 2.66 (d,J=7.4 Hz, 2H), 0.92-0.69 (m, 1H), 0.48-0.35 (m, 2H), 0.10 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+) 600.4 (M+1); (ES−) 634.3(M+Cl);1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51f) (160 mg) was converted to hydrochloride salt by dissolving thefree base in methanol (5 mL) and treating it with 10 equivalents of concHCl. The solution obtained was concentrated in vacuum to dryness driedin vacuum to furnish Racemic1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (51f) (100 mg, 53%) hydrochloride as a pale yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.87 (s, 1H), 9.27 (d,J=10.4 Hz, 1H), 8.58 (s, 3H), 8.20 (d, J=8.7 Hz, 1H), 8.07 (d, J=9.2 Hz,1H), 7.95 (dd, J=8.3, 1.4 Hz, 1H), 7.91 (s, 1H), 7.72 (t, J=1.8 Hz, 1H),7.69-7.36 (m, 10H), 6.35 (t, J=6.4 Hz, 1H), 4.10 (q, J=5.9 Hz, 2H), 4.03(s, 3H), 2.89 (dt, J=7.5, 4.4 Hz, 1H), 2.80-2.64 (m, 1H), 1.12 (ddd,J=12.4, 8.1, 4.9 Hz, 1H), 0.51 (dtt, J=17.5, 9.3, 4.6 Hz, 2H), 0.34-0.10(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+) 600.4 (M+1);(ES−) 634.3 (M+Cl); Analysis calculated for C₃₄H₃₂F₃N₅₀₂-2HCl 1.75H₂O:C, 58.00; H, 5.37; Cl, 10.07; N, 9.95; Found: C, 58.06; H, 5.45; Cl,9.93; N, 9.74.

Step-6: Preparation of(−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51g) and(+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51h)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(51f) (2 g) was separated using chiral preparative HPLC using CHIRALPAKAD-H column, 5 t, 4.6×250 mm, flow rate 1 mL/min, Solvent: 80%Hexane/20% IPA/0.1% DEA, UV=320 nM, 25° C., to furnish:

-   -   1. Peak-1        (−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51g) (904 mg, Rt=5.191 min, peak-1 for compound 51 g, 99.4822%,        Rt=8.194, peak-2 for compound 51h, 0.5178, 98.96% ee). This was        repurified by flash column chromatography (silica gel 25 g,        eluting 0-30% MeOH in chloroform for 25 mins) to afford        (−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51g) (730 mg, 99.38% ee) as a free base; Optical Rotation        −137.78 (MeOH, 1.645). To        (−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51g) free base (720 mg) was dissolved in methanol (8 mL) and        added 2 N HCl (in methanol, 2.25 mL, 10 eq.). The solution was        stirred at room temperature for 30 min, evaporated to dryness to        afford        (−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51g) (780 mg) hydrochloride salt as an off-white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.86        (dd, J=11.1, 8.1 Hz, 2H), 7.63 (s, 1H), 7.52 (q, J=3.1, 1.6 Hz,        3H), 7.47 (d, J=9.1 Hz, 1H), 7.43-7.26 (m, 5H), 7.18 (t, J=7.8        Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.89 (s, 1H), 3.86 (s, 3H),        3.76 (s, 2H), 2.11 (t, J=9.5 Hz, 1H), 0.92 (d, J=7.3 Hz, 1H),        0.42-0.27 (m, 2H), 0.08-0.02 (m, 1H), −0.04-−0.16 (m, 1H);        Analysis calculated for C₃₄H₃₂F₃N₅O₂.2HCl.2.5H₂O: C, 56.91; H,        5.48; Cl, 9.88; N, 9.76; Found; C, 57.14; H, 5.42; Cl, 9.47; N,        9.98.    -   2. Peak-2        (+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51h) (922 mg, Rt=5.271 min, peak-1 for compound 51 g, 0.25785%,        Rt=8.049, peak-2 for compound 51h, 99.4215, 97.67% ee). This was        repurified by flash column chromatography (silica gel 40 g,        eluting 0-30% MeOH in chloroform for 25 min) to afford        (+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51h) (0.753 g) free base as a white solid; Optical        Rotation+131.32 (MeOH, 2.695). To        (+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51h) (770 mg) of free base in methanol (25 mL) was added 2 N        HCl (in methanol, 6.5 mL, 10 eq.) stirred at room temperature        for 30 min and concentrated in vacuum to dryness to afford        (+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (51h) (753 mg) hydrochloride as an off-white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.98 (s, 1H, D₂O exchangeable), 9.88 (s, 1H,        D₂O exchangeable), 9.25 (s, 1H, D₂O exchangeable), 8.58 (s, 3H,        D₂O exchangeable), 8.20 (d, J=8.7 Hz, 1H), 8.07 (d, J=9.2 Hz,        1H), 7.99-7.87 (m, 2H), 7.72 (t, J=1.8 Hz, 1H), 7.70-7.54 (m,        6H), 7.53-7.39 (m, 3H), 6.50-6.19 (m, 1H), 4.10 (d, J=5.4 Hz,        2H), 4.03 (s, 3H), 2.89 (d, J=11.1 Hz, 1H), 2.73 (s, 1H), 1.13        (h, J=7.3, 6.8 Hz, 1H), 0.50 (ttd, J=13.2, 8.9, 4.3 Hz, 2H),        0.23 (ddq, J=18.4, 9.2, 4.6 Hz, 2H); 1H NMR (300 MHz, DMSO-d₆        D₂O) δ 8.19 (d, J=8.8 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.96 (dd,        J=8.3, 1.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.71 (t, J=1.8 Hz,        1H), 7.66-7.55 (m, 6H), 7.54-7.38 (m, 4H), 6.34 (s, 1H), 4.12        (s, 2H), 4.03 (s, 3H), 2.91 (dd, J=12.9, 6.8 Hz, 1H), 2.73 (dd,        J=13.0, 7.6 Hz, 1H), 1.08 (q, J=6.1, 5.0 Hz, 1H), 0.53 (dtd,        J=17.3, 9.4, 8.9, 4.7 Hz, 2H), 0.23 (dhept, J=18.0, 4.7 Hz, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.74; MS (ES+) 600.3 (M+1), MS        (ES−) 598.3 (M−1), 634.3 (M+Cl); Analysis calculated for        C₃₄H₃₂F₃N₅O₂.2HCl.2.75H₂O: C, 56.55; H, 5.51; Cl, 9.82; N, 9.70;        Found; C, 56.42; H, 5.40; Cl, 10.26; N, 9.66.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h) Step-1: Preparation ofN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(52b)

To a stirred solution of 5-bromo-2-fluoroaniline (52a) (225 g, 1184mmol) in triethylamine (3301 mL, 20 eq) was added trimethylsilyltrifluoromethanesulfonate (481 mL, 2664 mmol) at room temperature [Note:during the addition heat was generated but, was not needed to cool theflask]. The mixture was heated at reflux for 16 h and cooled to roomtemperature. The two layers were separated. [Note: avoid exposing thesolution to air or moisture during the separation]. Dark bottom solutionwas discarded and the upper layer was concentrated in vacuum to removeexcess triethylamine. The oily residue was transferred to 1000 mL flaskand distilled under high vacuum. The compound starts to distill at 100°C. at 0.5 mm/Hg. First fraction (about 15 mL) was discarded the secondfraction was collected steadily at 100° C., 0.5 mm/Hg, to furnishN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(52b) (364 g, 1089 mmol, 92% yield). This was always freshly preparedfor next step; ¹H NMR (300 MHz, Chloroform-d) δ 7.17-7.11 (m, 1H), 7.09(dd, J=7.5, 2.5 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 0.08 (d, J=0.6 Hz,18H).

Step-2: Preparation of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium Bromide (52c)

To magnesium turnings (33.1 g, 1361 mmol) in tetrahydrofuran (15 mL) wasadded iodine (1.381 g, 5.44 mmol) followed byN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(52b) (4g) to activate the reaction for about 5 minutes (Iodine colorwas decolorized). At this point rest of the solution ofN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(52b) (364 g, 1089 mmol) in tetrahydrofuran (1000 mL) was added slowlyin over a period of 3 h (reaction temperature was around 60° C. duringthe addition. The resulting dark grey solution was stirred overnight tofurnish (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide(52c) (397 g, 1107 mmol, 102% yield, approximately 1 M solution) whichwas used fresh in the next step.

Step-3: Preparation of4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (52e)

To a solution of 4-formylbenzonitrile (52d) (6.56 g, 50 mmol) intetrahydrofuran (50 mL) cooled to 0° C. was added Grignard reagent (52c)(63.0 mL, 50.4 mmol, −0.8 M in THF) stirred at 0° C. for 1 h, and roomtemperature for 17 h. The reaction mixture was quenched with 1 N HCl(aq. 100 mL), stirred for 3 h, neutralized with NaOH (2 N, aq.) topH=˜8. The reaction mixture was extracted with ethyl acetate (200, 150mL). The combined extracts were washed with brine (120 mL), dried overMgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel, eluting withchloroform/methanol (1:0 to 19:1)] to afford4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (52e) (6.37 g)as a brown gum, which was used as such for next step). MS (ES+): 265.2(M+23).

Step-4: Preparation of tert-butyl3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52f)

To a solution of 4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile(52e) (3 g, 12.38 mmol) in DMF (80 mL) was added1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (4.77 g, 12.38 mmol), N-ethyl-N-isopropylpropan-2-amine(18.00 mL, 103 mmol), bromotripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBrOP, 5.94 g, 12.48 mmol) and stirred at roomtemperature for 19 h. The reaction mixture was diluted with ethylacetate (400 mL), washed with water (200, 150 mL), brine (150 mL), driedover MgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel 120 g, eluting withhexanes/ethyl acetate (1:0 to 1:1)] to afford tert-butyl3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52f) (1.998 g) as a light yellow solid, which was used as such for nextstep; MS (ES+): 632.3 (M+23).

Step-5: Preparation of tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52g)

To a solution of tert-butyl3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52f) (1.007 g, 1.652 mmol) in dichloromethane (32 mL) at 0° C. wasadded thionyl chloride (0.260 mL, 3.52 mmol) and warmed to roomtemperature over 2 h. The reaction mixture was quenched with triethylamine (1.5 mL, 10.76 mmol) stirred at room temperature for 1 h. It wasthen treated with cyclopropylmethanamine (3.20 mL, 35.8 mmol),concentrated to remove most of dichloromethane followed by addition ofacetonitrile (24 mL), stirring at 70° C. for 19 h, and concentration invacuum to dryness. The residue was treated with chloroform (200 mL),washed with water (100 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to2:1)] to afford tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52g) (244 mg, 3% for three steps) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.56 (s, 1H), 7.80-7.73 (m, 2H), 7.67-7.29 (m, 10H),7.26-7.17 (m, 1H), 4.95 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.25 (d, J=6.9Hz, 2H), 1.37 (s, 9H), 0.98-0.79 (m, 1H), 0.43-0.27 (m, 2H), 0.09-−0.02(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −123.20; MS (ES+): 663.4(M+1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h)

To a solution of tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52g) (85 mg, 0.128 mmol) in 1,4-Dioxane (9 mL) was added hydrogenchloride (1.400 mL, 5.60 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 18 h. the reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h) (40 mg, 55%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.82(s, 1H), 10.43 (s, 2H), 8.42 (s, 3H), 7.95 (s, 5H), 7.78-7.66 (m, 3H),7.62 (dt, J=7.3, 1.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.55-7.49 (m, 1H),7.48-7.36 (m, 1H), 5.81 (d, J=6.9 Hz, 1H), 4.13 (d, J=5.3 Hz, 2H),2.84-2.63 (m, 2H), 1.28-1.03 (m, 1H), 0.66-0.45 (m, 2H), 0.44-0.14 (m,2H); ¹H NMR (300 MHz, DMSO-d₆, D₂O ex NMR) δ 7.95 (d, J=8.2 Hz, 2H),7.90-7.78 (m, 3H), 7.70 (s, 1H), 7.65 (s, 1H), 7.62-7.48 (m, 4H), 7.43(t, J=9.4 Hz, 1H), 5.77 (s, 1H), 4.12 (s, 2H), 2.74 (d, J=7.3 Hz, 2H),1.15-1.00 (m, 1H), 0.58 (d, J=7.6 Hz, 2H), 0.29 (d, J=4.9 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.82, −120.00; MS (ES+): 563.3 (M+1).1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h) (21 mg) was dissolved in methanol (10 mL) and treated with 4 N HCl(aq. 0.04 mL) followed by concentration to dryness to give HCl salt of1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h) (21 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.98-7.91(m, 2H), 7.90-7.79 (m, 3H), 7.73-7.49 (m, 7H), 7.43 (dd, J=10.2, 8.6 Hz,1H), 5.77 (s, 1H), 4.12 (s, 2H), 2.75 (d, J=7.0 Hz, 2H), 1.14-1.00 (m,1H), 0.64-0.54 (m, 2H), 0.33-0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.81, −119.99; MS (ES+): 563.3 (M+1); Analysis calculated forC₃₀H₂₆F₄N₆O.2.0HCl.2.5H₂O: C, 52.95; H, 4.89; N, 12.35; Found: C, 53.21;H, 4.95; N, 11.71.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53f) Step-1: Preparation of (3-aminophenyl)(3-nitrophenyl)methanol(53b)

To a stirred solution of 3-nitrobenzaldehyde (53a) (3.02 g, 20 mmol) intetrahydrofuran (20 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24.00 mL,24.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding hydrogen chloride (12N) (4.17 mL,50.0 mmol), stirred for 1 h. The reaction mixture was treated withsodium hydroxide (2N) (30.0 mL, 60.0 mmol) and extracted with ethylacetate (2×50 mL). The organic layers were combined washed with sat.NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered and evaporated todryness. The crude residue was purified by flash column chromatography(silica gel 120 g, eluting with 0-100% ethyl acetate in hexane) tofurnish (3-aminophenyl)(3-nitrophenyl)methanol (53b) (966 mg) as a brownsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (t, J=2.0 Hz, 1H), 8.08 (ddd,J=8.2, 2.4, 1.1 Hz, 1H), 7.78 (ddt, J=7.6, 1.6, 0.8 Hz, 1H), 7.60 (t,J=7.9 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.62-6.51 (m, 2H), 6.41 (ddd,J=7.9, 2.3, 1.0 Hz, 1H), 6.07 (d, J=3.9 Hz, 1H), 5.68 (d, J=3.9 Hz, 1H),5.06 (s, 2H); MS (ES+) 245.2 (M+1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53c)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1101 mg, 3.91 mmol), (3-aminophenyl)(3-nitrophenyl)methanol (53b) (956mg, 3.91 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (1862 mg, 3.91 mmol) was addedN,N-dimethylformamide (DMF) (22 mL) andN-ethyl-N-isopropylpropan-2-amine (DIPEA) (5.50 mL, 31.6 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 13 hunder a positive flow of nitrogen atmosphere. The reaction mixture wasdiluted with ethyl acetate (180 mL), washed with water (2×80 mL), brine(80 mL), dried over MgSO₄ filtered and and concentrated in vacuum todryness. The crude product was purified by flash column chromatography[silica gel 40 g, eluting with hexanes/ethyl acetate (1:0 to 1:1)] togive1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53c) (1.102 g, 56%) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66(s, 1H), 8.24 (t, J=1.9 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.10 (ddd,J=8.1, 2.4, 1.1 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2,2.2, 1.1 Hz, 1H), 7.83-7.55 (m, 6H), 7.31 (t, J=7.8 Hz, 1H), 7.20 (dt,J=7.8, 1.3 Hz, 1H), 6.32 (d, J=4.0 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES+) 530.2 (M+23).

Step-3: Preparation of tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53d)

A solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53c) (0.865 g, 1.705 mmol) in MeOH (30 mL) was cooled with ice/waterand treated with di-tert-butyl dicarbonate (1.503 g, 6.82 mmol) andnickel(II) chloride hexahydrate (0.218 g, 0.917 mmol) followed byaddition of sodium borohydride (0.658 g, 17.05 mmol) slowly over 5 minand stirring at room temperature for 1 h. The reaction mixture wastreated N1-(2-aminoethyl)ethane-1,2-diamine (0.840 mL, 7.70 mmol)followed by stirring at room temperature for 0.5 h and concentration todryness. The residue was treated with ethyl acetate (120 mL), washedwith water (80 mL). The aqueous phase was extracted again with ethylacetate (80 mL). The combined extracts were washed with brine (80 mL),dried over MgSO₄ followed by filtration and concentration. The crudeproduct was purified by flash column chromatography [silica gel withhexanes/ethyl acetate (1:0 to 1:1)] to afford tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53d) (547 mg, 47%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 9.30 (s, 1H), 7.57 (s, 2H), 7.55-7.08 (m, 11H), 6.93 (d,J=7.5 Hz, 1H), 5.90 (d, J=3.7 Hz, 1H), 5.57 (d, J=3.7 Hz, 1H), 4.19 (d,J=6.2 Hz, 2H), 1.45 (s, 9H), 1.36 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.79; (ES+) 704.4 (M+23).

Step-4: Preparation of tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53e)

To a solution of tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53d) (531 mg, 0.779 mmol) in dichloromethane (15 mL) at 0° C. was addedthionyl chloride (0.110 mL, 1.511 mmol), reaction mixture allowed towarm to room temperature and stirred for 12 h. The reaction mixture wasquenched with cyclopropylmethanol (5.80 mL, 70.1 mmol), stirred for 1 hat room temperature and concentrated in vacuum to dryness. The residuewas dissolved in cyclopropylmethanol (5.80 mL, 70.1 mmol) addedtriethylamine (0.660 mL, 4.74 mmol) and heated at 100° C. for 13 h. Thereaction mixture was cooled to room temperature and evaporated todryness. The residue was dissolved in ethyl acetate (150 mL) and washedwith water (80 mL), brine (70 mL), dried over MgSO₄ followed byfiltration and concentration. The residue was purified by flash columnchromatography [(silica gel 12 g, eluting with hexanes/ethyl acetate(1:0 to 2:1)] to give tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53e) (243 mg, 42%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.74 (s, 1H), 9.34 (s, 1H), 7.62-7.25 (m, 11H), 7.19 (t, J=7.8 Hz, 1H),7.10 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 5.36 (s, 1H), 4.19 (d,J=6.2 Hz, 2H), 3.27-3.15 (m, 2H), 1.45 (s, 9H), 1.36 (s, 9H), 1.12-0.97(m, 1H), 0.52-0.39 (m, 2H), 0.21-0.10 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.79; (ES+) 758.4 (M+23).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53f)

To a solution of tert-butyl3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(53e) in methanol (20 mL) was added conc. hydrogen chloride (0.230 mL,2.76 mmol) and stirred at room temperature for 13 h. The reactionmixture was concentrated to dryness under vacuum (at <30° C.). Theresidue was purified by flash column chromatography [silica gel elutingwith chloroform/CMA80 (1:0 to 3:1)] to1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53f) (84 mg) as free base. The purified product was dissolved inmethanol (10 mL) and treated with 4 N HCl (aq. 0.16 mL) followed byconcentration to dryness to give HCl salt of1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53f) (91 mg, 55%) as a white solid; ¹H NMR (D₂O ex NMR, 300 MHz,DMSO-d6) δ 7.56-7.33 (m, 7H), 7.21-7.10 (m, 2H), 6.98 (d, J=7.6 Hz, 1H),6.90 (bs, 2H), 6.78 (d, J=8.1 Hz, 1H), 5.26 (s, 1H), 3.97 (s, 2H), 3.08(dd, J=6.9, 1.3 Hz, 2H), 0.97-0.81 (m, 1H), 0.40-0.26 (m, 2H),0.08-−0.07 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+) 536.3(M+1); Analysis calculated for C₂₉H₂₈F₃N₅O₂.2.0HCl.2.0H₂O: C, 54.04; H,5.32; N, 10.87; Found: C, 53.63; H, 5.19; N, 10.78.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(54e) Step-1: Preparation of3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b)

To a solution of 3-formylbenzonitrile (54a) (29 g, 217 mmol) intetrahydrofuran (200 mL) cooled to 0° C. was added freshly preparedGrignard reagent (52c) (245 mL, 221 mmol, 0.9 M in THF) stirred at 0° C.for 1 h, and room temperature for 18 h. The reaction mixture wasquenched with 1 N HCl (aq. 440 mL), stirred for 3 h, neutralized withNaOH (2 N, aq.) to pH=8. The reaction mixture was extracted with ethylacetate (600, 300 mL). The combined extracts were washed with brine (120mL), dried over MgSO₄, filtered and concentrated in vacuum. The crudeproduct was purified by flash column chromatography [silica gel, elutingwith hexanes/ethyl acetate (1:0 to 1:1) to give3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (36.28 g)as a brown gum which was used as such for next step; MS (ES+) 265.3(M+23).

Step-2: Preparation of tert-butyl3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54c)

To a solution of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile(54b) (24.682 g, 102 mmol) in DMF (480 mL) was added1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (35.0 g, 91 mmol), N-ethyl-N-isopropylpropan-2-amine (132 mL,758 mmol), bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 42.8 g, 91 mmol) and stirred at room temperature for 19 h. Thereaction mixture was diluted with ethyl acetate (1000 mL), washed withwater (500, 400 mL), brine (400 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to1:1)] to afford tert-butyl3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54c) (4.583 g, 5% for two steps) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.57 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.73-7.66 (m, 2H),7.64-7.19 (m, 10H), 6.25 (d, J=4.0 Hz, 1H), 5.78 (d, J=4.0 Hz, 1H), 4.19(d, J=6.1 Hz, 2H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81,−123.09; MS (ES+) 632.3 (M+23).

Step-3: Preparation of tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54d)

To a solution of tert-butyl3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54c) (1.333 g, 2.187 mmol) in dichloromethane (40 mL) at 0° C. wasadded thionyl chloride (0.340 mL, 4.59 mmol) and warmed to roomtemperature over 2 h. The reaction mixture was quenched with triethylamine (2.0 mL, 14.35 mmol) stirred at room temperature for 1 h. It wasthen treated with cyclopropylmethanamine (4.30 mL, 48.0 mmol),concentrated to remove most of dichloromethane followed by addition ofacetonitrile (30 mL), stirring at 70° C. for 14 h, and concentration invacuum to dryness. The residue was treated with chloroform (200 mL),washed with water (100 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to2:1)] to afford tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54d) (184 mg, 13%) as colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.56(s, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.70-7.30 (m, 10H),7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J=6.2 Hz, 2H),2.26 (d, J=6.6 Hz, 2H), 1.37 (s, 9H), 1.00-0.80 (m, 1H), 0.45-0.28 (m,2H), 0.12-−0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −123.20;MS (ES+) 663.4 (M+1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(54e)

To a solution of tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54d) (161 mg, 0.243 mmol) in 1,4-Dioxane (18 mL) was added hydrogenchloride (2.60 mL, 10.40 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 16 h. the reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 2:1)] to afford1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(54e). The pure product was dissolved in methanol (10 mL) and added 4 NHCl (aq. 0.14 mL) followed by concentration in vacuum to dryness to giveHCl salt of1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(54e) (74 mg, 48%) white solid; ¹H NMR (300 MHz, DMSO-d₆, D₂O ex NMR) δ8.13 (t, J=1.7 Hz, 1H), 7.98-7.84 (m, 3H), 7.73-7.64 (m, 3H), 7.63-7.48(m, 4H), 7.44 (dd, J=10.2, 8.6 Hz, 1H), 5.75 (s, 1H), 4.12 (s, 2H), 2.76(d, J=7.2 Hz, 2H), 1.17-0.94 (m, 1H), 0.68-0.47 (m, 2H), 0.34-0.24 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −120.02; MS (ES+): 563.3(M+1); Analysis calculated for C₃₀H₂₆F₄N₆O.2.0HCl.3.0H₂O: C, 52.26; H,4.97; N, 12.19; Found: C, 52.26; H, 5.00; N, 11.72.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(55b) Step-1: Preparation of tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(55a)

To a solution of tert-butyl3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52f) (5.4 g, 8.86 mmol) in dichloromethane (50 mL) and triethylamine(7.51 mL, 53.9 mmol) at 0° C. was added thionyl chloride (1.254 mL,17.19 mmol), reaction mixture was allowed to warm to room temperatureand stirred for 1.5 h. The reaction mixture was quenched withtriethylamine (7.51 mL, 53.9 mmol), cyclopropylmethanol (26.4 mL, 319mmol) and heated with stirring at 105° C. for 13 h. The reaction mixturewas cooled to room temperature and evaporated to dryness. To the residuewas added water (100 mL) and extracted with chloroform (2×75 mL). Theorganic layers were combined washed with brine (70 mL), dried over MgSO₄followed by filtration and concentration. The residue obtained waspurified by flash column chromatography (silica gel 80 g, eluting withhexanes/ethyl acetate 0 to 100%) to furnish tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(55a) (0.308 g, 5.24% yield) as a yellow solid. MS (ES+): 632.3 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(55b)

To a stirred solution of furnish tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(55a) (43 mg, 0.065 mmol) in methanol (5 mL) was added hydrochloric acid(2 M solution in methanol, 0.648 mL, 1.296 mmol) at room temperature andstirred for 18 h. The reaction was concentrated to remove excesshydrochloric acid. The residue was purified by flash columnchromatography (silica gel 12 g, eluting with methanol in chloroform0-50%) to afford pure1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(55b) (18 mg, 49.3%) as a white solid; ¹H NMR (300 MHz, DMSO-d6) δ 10.62(s, 1H, D₂O exchangeable), 7.82 (d, J=8.3 Hz, 2H), 7.56 (dt, J=12.3, 6.2Hz, 5H), 7.44 (d, J=7.0 Hz, 2H), 7.34 (d, J=7.2 Hz, 1H), 7.27 (d, J=7.8Hz, 2H), 5.61 (s, 1H), 3.80 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.05 (s,1H), 0.51-0.40 (m, 2H), 0.20-0.08 (m, 2H); MS (ES+) 564.3 (M+1), (ES−)562.3 (M−1), 598.2 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (56c)Step-1: Preparation of tert-butyl3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56a)

To a solution of tert-butyl3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(54c) (1.333 g, 2.187 mmol) in dichloromethane (40 mL) at 0° C. wasadded thionyl chloride (0.34 mL, 4.59 mmol) and warmed to roomtemperature over 2 h. The reaction mixture was treated with triethylamine (2.000 mL, 14.35 mmol) stirred at room temperature for 1 h. It wasthen treated with cyclopropylmethanamine (4.30 mL, 48.0 mmol) andconcentrated to remove most of dichloromethane followed by addition ofacetonitrile (30 mL), stirring at 70° C. for 14 h, and concentration todryness. The residue was treated with chloroform (200 mL), washed withwater (100 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to2:1)] to afford;

-   -   1. tert-butyl        3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (54d) (184 mg, 13%) as a colorless gum; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.56 (s, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.77-7.71 (m,        1H), 7.70-7.30 (m, 10H), 7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s,        1H), 4.19 (d, J=6.2 Hz, 2H), 2.26 (d, J=6.6 Hz, 2H), 1.37 (s,        9H), 1.00-0.80 (m, 1H), 0.45-0.28 (m, 2H), 0.12-−0.01 (m, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −123.20; MS (ES+) 663.4        (M+1).    -   2. tert-butyl        3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (56a) (300 mg, 22%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)        δ 10.67 (s, 1H), 7.95 (t, J=1.7 Hz, 1H), 7.86-7.74 (m, 3H),        7.67-7.58 (m, 2H), 7.54-7.28 (m, 7H), 6.64 (s, 1H), 4.19 (d,        J=6.2 Hz, 2H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.82, −120.97; MS (ES+) 650.3 (M+23).

Step-2: Preparation of tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56b)

A solution of tert-butyl3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56a) (0.26 g, 0.414 mmol) was treated with cyclopropylmethanol (3.10mL, 37.5 mmol) and triethylamine (0.470 mL, 3.37 mmol) followed bystirring at 100° C. for 15 h. The reaction mixture was diluted withethyl acetate (120 mL) and washed with water (75 mL). The organic layerwas washed with brine (60 mL), dried over MgSO₄ followed by filtrationand concentration. The crude product was purified by flash columnchromatography [silica gel with hexanes/ethyl acetate (1:0 to 2:1)] tofurnish tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56b) (243 mg, 88%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 7.82 (t, 1H), 7.74 (dt, J=7.5, 1.5 Hz, 1H), 7.71-7.66 (m,1H), 7.64-7.22 (m, 10H), 5.59 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 3.24 (d,J=6.8 Hz, 2H), 1.37 (s, 9H), 1.12-0.99 (m, 1H), 0.54-0.39 (m, 2H),0.22-0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −122.30; MS(ES+) 686.4 (M+23).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(56c)

To a solution of tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56b) (220 mg, 0.331 mmol) in methanol (24 mL) was added conc. hydrogenchloride (0.170 mL, 2.039 mmol) followed by stirring at room temperaturefor 23.5 h and concentration under vacuum (at <30 OC). The residueobtained was purified by flash column chromatography [silica gel 4 g,eluting with chloroform/CMA80 (1:0 to 3:1) to afford1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(56c) (133 mg, 71%) free base as a colorless gum. The purified product(69 mg) was dissolved in methanol (10 mL) and then treated with 4 N HCl(aq. 0.12 mL) followed by concentration to dryness to give HCl salt ofcolorless gum, (78 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.67 (s, 1H), 8.38 (s, 3H), 7.81 (t, J=1.7 Hz, 1H), 7.76-7.66 (m, 4H),7.63-7.47 (m, 6H), 7.37-7.23 (m, 2H), 5.59 (s, 1H), 4.11 (q, J=5.8 Hz,2H), 3.29-3.20 (m, 2H), 1.15-0.95 (m, 1H), 0.54-0.37 (m, 2H), 0.27-0.04(m, 2H); ¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (t, J=1.6 Hz, 1H), 7.74 (dt,J=7.6, 1.5 Hz, 1H), 7.72-7.66 (m, 2H), 7.64 (s, 1H), 7.62-7.49 (m, 5H),7.36-7.23 (m, 2H), 5.59 (s, 1H), 4.12 (s, 2H), 3.26-3.23 (m, 2H),1.14-0.95 (m, 1H), 0.54-0.39 (m, 2H), 0.18-0.11 (m, 2H). ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.82, −121.88; MS (ES+) 564.3 (M+1); (ES−) 562.3(M−1); HPLC (94.54%, t_(R)=19.943 min); Analysis calculated forC₃₀H₂₅F₄N₅O₂.1.0HCl.1.25H₂O: C, 57.88; H, 4.61; N, 11.25; Found: C,57.90; H, 4.57; N, 11.19.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e) Step-1: (3-amino-4-fluorophenyl)(3-nitrophenyl)methanol (57a)

To a stirred solution of 3-nitrobenzaldehyde (53a) (25.7 g, 170 mmol) intetrahydrofuran (150 mL) was added freshly prepared(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(170 mL, 170 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding hydrogen chloride (2N, 213 mL, 425mmol) at 0° C., stirred for 1 h, TLC analysis (ethyl acetate/hexanes,1/1, v/v) shows reaction was complete. The reaction mixture was treatedwith sodium hydroxide (2 N, 255 mL, 510 mmol) and extracted with ethylacetate (3×750 mL). The organic layers were combined dried overanhydrous MgSO₄, filtered, and evaporated to dryness. The crude residuewas purified by flash column chromatography (silica gel 1 kg, elutingwith 0-70% ethyl acetate in hexane) to furnish(3-amino-4-fluorophenyl)(3-nitrophenyl)methanol (57a) (4.638 g, 10%yield) as a dark brown syrup.

¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (t, J=2.0 Hz, 1H), 8.08 (ddd, J=8.1,2.5, 1.1 Hz, 1H), 7.77 (dt, J=7.2, 1.4 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H),6.91 (dd, J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=8.9, 2.2 Hz, 1H), 6.55 (ddd,J=8.4, 4.4, 2.2 Hz, 1H), 6.13 (d, J=3.9 Hz, 1H), 5.71 (d, J=3.8 Hz, 1H),5.13 (s, 2H); MS (ES⁺): MS (ES+) 263.1 (M+1), MS (ES−) 523.2 (2M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57b)

In a 500 mL single-necked flask1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(5.91 g, 21.00 mmol), (3-amino-4-fluorophenyl)(3-nitrophenyl)methanol(57a) (4.59 g, 17.50 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP, 9.79 g, 21.00 mmol) were treatedwith N,N-dimethylformamide (102 mL,) andN-ethyl-N-isopropylpropan-2-amine (15.24 mL, 88 mmol) successively in apositive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. The residue was diluted with ethyl acetate (250mL), and layer was separated with water (1 L), aq. layer was againextracted with ethyl acetate (500 mL), combined organics were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue waspurified by flash column chromatography [silica gel 120 g, eluting withethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57b) (2.641 g, 29% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.56 (s, 1H), 8.24 (t, J=2.0 Hz, 1H), 8.15-8.06 (m, 2H), 7.99 (dt,J=7.8, 1.3 Hz, 1H), 7.93-7.86 (m, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.77-7.68(m, 2H), 7.67-7.54 (m, 2H), 7.39-7.19 (m, 2H), 6.36 (d, J=4.1 Hz, 1H),5.90 (d, J=4.0 Hz, 1H); MS (ES⁺): MS (ES+) 548.2 (M+Na), MS (ES−) 524.7(M−1); 560.3 (M+Cl).

Step-3: Preparation of tert-butyl3-(5-((5-((3-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57c)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57b) (2.25 g, 4.28 mmol) in anhydrous methanol (60 mL), cooled to 0°C., were added di-tert-butyl dicarbonate (3.74 g, 17.13 mmol) andstirred for 10 min. Nickel(II) chloride hexahydrate (0.763 g, 3.21mmol), sodium borohydride (1.620 g, 42.8 mmol) was then added in smallportions over a period of 4 h. The reaction was exothermic andeffervescent. The reaction mixture was stirred for 45 min at 0° C., atthis point N1-(2-aminoethyl)ethane-1,2-diamine (4.63 mL, 42.8 mmol) wasadded. The mixture was allowed to stir for additional 30 mins beforesolvent was evaporated. The residue was treated with water (75 mL), andextracted with chloroform (2×100 mL) combined organic layers were driedover anhydrous MgSO₄, filtered, excess solvents were pumped-off underreduced pressure. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with methanol/chloroform from0 to 50%)] to furnish tert-butyl3-(5-((5-((3-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57c) (0.963 g, 1.376 mmol, 32.1% yield) as a light red solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.55 (s, 1H), 9.30 (s, 1H), 7.61-7.31 (m, 7H),7.29-7.12 (m, 4H), 6.92 (d, J=7.6 Hz, 1H), 5.96 (d, J=3.8 Hz, 1H), 5.60(d, J=3.9 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.45 (s, 9H), 1.38 (s, 9H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.79, −123.57; MS (ES⁺): MS (ES+) 722.3(M+Na).

Step-4: Preparation of tert-butyl3-(5-((5-((tert-butoxycarbonyl-3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57d)

A solution of tert-butyl3-(5-((5-((3-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57c) (1.1 g, 1.572 mmol) in dichloromethane (20 mL) at 0° C. wastreated with thionyl chloride (0.222 mL, 3.05 mmol) and allowed to warmto room temperature and stirred for 2.5 h. The solution was treated withtriethylamine (1.332 mL, 9.56 mmol) followed by stirring at roomtemperature for 30 min, to this cyclopropylmethanol (11.70 mL, 141 mmol)and triethylamine (1.332 mL, 9.56 mmol) was added, concentrated toremove most of dichloromethane followed by addition of moretriethylamine (1.332 mL, 9.56 mmol) and stirring at 115° C. for 11 h.The reacuon mixture was cooled and concentrated to dryness. The residueobtained was treated with water (25 mL) and extracted with chloroform(2×30 mL). The combined organic layers were dried over MgSO₄, filtered,evaporated to dryness. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0 to 100%)] to furnish tert-butyl3-(5-((5-((tert-butoxycarbonyl-3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57d) (0.521 g, 0.691 mmol, 44.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O exchangeable), 9.35 (s, 1H), 7.58 (s,1H), 7.56-7.45 (m, 3H), 7.42 (d, J=7.4 Hz, 2H), 7.38-7.32 (m, 2H), 7.23(dq, J=20.3, 7.8 Hz, 4H), 6.92 (d, J=7.4 Hz, 1H), 5.39 (s, 1H), 4.19 (d,J=6.2 Hz, 2H), 3.21 (dd, J=6.8, 3.1 Hz, 2H), 1.45 (s, 9H), 1.37 (s, 9H),1.03 (d, J=7.8 Hz, 1H), 0.45 (dt, J=8.7, 2.9 Hz, 2H), 0.16 (dd, J=5.6,3.9 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −122.72; MS (ES⁺): MS(ES+) 776.4 (M+Na), MS (ES−) 752.3 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e)

To a solution of tert-butyl3-(5-((5-((tert-butoxycarbonyl-3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57d) (0.511 g, 0.678 mmol) in methanol (20 mL) was added drop-wiseconc. hydrogen chloride (12 N HCl) (1.412 mL, 16.95 mmol) followed bystirring at room temperature for 14 h. Excess solvent was pumped-offunder reduced pressure. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with CMA80 in chloroform from0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e) (0.261 g, 70% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.59 (s, 1H, D₂O exchangeable), 7.59 (d, J=8.8 Hz, 2H),7.55-7.45 (m, 3H), 7.44-7.35 (m, 1H), 7.30-7.15 (m, 2H), 6.94 (t, J=7.7Hz, 1H), 6.52 (t, J=1.9 Hz, 1H), 6.50-6.36 (m, 2H), 5.26 (s, 1H), 5.08(s, 2H, D₂O exchangeable), 3.89 (s, 2H), 3.19 (dd, J=6.8, 2.7 Hz, 2H),1.11-0.94 (m, 1H), 0.54-0.38 (m, 2H), 0.23-0.08 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.76, −123.05; MS (ES⁺): MS (ES+) 554.3 (M+1), 588.2(M−1).

A solution of1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e) freebase (20 mg, 0.036 mmol) in methanol (2 mL) was treated withhydrogen chloride (0.217 mL, 0.434 mmol) followed by stirring at roomtemperature for 10 min. Excess solvent was pumped-off under reducedpressure to furnish1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e) (22 mg, 97%) hydrochloride salt as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.35 (s, 4H), 7.72 (s, 1H), 7.68 (s, 1H),7.64-7.47 (m, 5H), 7.36-7.21 (m, 3H), 7.10 (s, 2H), 7.00 (s, 2H), 5.47(s, 1H), 4.12 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.15-0.97 (m, 1H),0.55-0.35 (m, 2H), 0.23-0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.82, −122.33; MS (ES⁺): MS (ES+) 554.3 (M+1), 576.3 (M+Na), 552.3(M−1), 588.2 (M+Cl); Analysis calculated for: C₂₉H₂₇F₄N₅O₂.1.75H₂O.2HCl:C, 53.30; H, 4.94; N, 10.72; Found: C, 53.37; H, 4.79; N, 10.67.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58c) Step-1: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol(58a)

To a stirred solution of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one(47c) (12 g, 68.5 mmol) in tetrahydrofuran (100 mL) was added freshlyprepared (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide(52c) (88 mL, 79 mmol) at 0° C. The reaction was allowed to come to roomtemperature for 12 h, quenched by adding hydrogen chloride (2N, 100 mL,200 mmol) at 0° C., stirred for 1 h, TLC analysis (ethylacetate/hexanes, 1/1, v/v) shows reaction was complete. The reactionmixture was treated with sodium hydroxide (2N, 105 mL, 210 mmol) andextracted with ethyl acetate (3×150 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered, and evaporated todryness. The crude residue was purified by flash column chromatography(silica gel 120 g, eluting with 0-100% ethyl acetate in hexane) tofurnish1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol(58a) (15.3 g, 78%) as a brown semisolid; MS (ES+) 309.2 (M+Na), (ES−)285.2 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(11.99 g, 42.6 mmol) in N,N-dimethylformamide (257 mL, 3326 mmol) wasadded1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol(58b) (14.65 g, 51.2 mmol), N-ethyl-N-isopropylpropan-2-amine (59.4 mL,341 mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBroP) (21.86 g, 46.9 mmol) at room temperature. The resultingreaction mixture was stirred at 25° C. for 16 h. The reaction mixturewas diluted with water (1000 mL) and extracted with ethyl acetate(3×1000 mL), washed with water (2×500 mL), brine (300 mL). The organiclayers were combined dried over anhydrous MgSO₄, filtered, concentratedunder reduced pressure to dryness. The residue was purified by flashcolumn chromatography [silica gel 80 g, eluting with a (9:1)ethylacetate: methanol mixture in hexanes 0 to 50%] to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58b) (19.9 g, 85% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.54 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.7, 1.6 Hz, 1H),8.12 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.95-7.86 (m, 1H),7.82-7.69 (m, 3H), 7.61 (dd, J=7.6, 2.3 Hz, 1H), 7.40-7.27 (m, 2H), 7.21(dd, J=10.2, 8.7 Hz, 1H), 5.81 (s, 1H), 2.34 (t, J=8.0 Hz, 2H), 1.05 (d,J=13.9 Hz, 2H), 0.64 (h, J=6.6 Hz, 1H), 0.40-0.28 (m, 2H), −0.07 (dd,J=4.9, 1.6 Hz, 2H); MS (ES+): 550.3 (M+1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58c)

To a stirred solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58b) (10 g, 18.20 mmol) in Methanol (300 mL) at 0° C. was addednickel(II) chloride hexahydrate (5.41 g, 22.75 mmol). To this sodiumtetrahydroborate (6.88 g, 182 mmol) was added in small portions over aperiod of 15 minutes. The reaction was stirred for 30 minutes andquenched by adding N1-(2-aminoethyl)ethane-1,2-diamine (15.09 mL, 146mmol) and stirred for 30 minutes at room temperature. The reactionmixture was concentrated to remove methanol. The reaction mixture wasdiluted with water (200 mL) and stirred for 30 minutes. The solidseparated collected by filtration. The solid was suspended in ethanol(100 mL) and concentrated to dryness to remove water. The residue wasdissolved in methanol and purified by flash column chromatography(silica gel 40 g, eluting with CMA 80 in chloroform 0-100%) to affordpure1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58c) (2.56 g, 25.4% yield) as a colorless solid. ¹HNMR (300 MHz,DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.62 (dd, J=2.4, 0.9 Hz,1H), 8.38 (dd, J=4.7, 1.6 Hz, 1H), 7.77 (dt, J=8.1, 1.9 Hz, 1H),7.69-7.62 (m, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.48-7.38 (m, 2H),7.39-7.27 (m, 3H), 7.25-7.15 (m, 1H), 5.80 (s, 1H, D₂O exchangeable),3.78 (s, 2H), 2.33 (t, J=7.9 Hz, 2H), 1.13-1.02 (m, 2H), 0.63 (p, J=7.3,6.5 Hz, 1H), 0.39-0.28 (m, 2H), −0.07 (dt, J=5.5, 2.8 Hz, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.73, −123.95; MS (ES+): 554.3 (M+1); Analysiscalculated for C₂₉H₂₇F₄N₅O₂.1.5H₂O: C, 59.99; H, 5.21; N, 12.06; Found:C, 60.07; H, 4.86; N, 11.68.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59c) Step-1: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a)

To a stirred solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one(45d) (13.09 g, 74.7 mmol) in tetrahydrofuran (50 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (93mL, 93 mmol) at 0° C. The reaction was allowed to come to roomtemperature and stirred for 12 hrs at same temperature. The reaction wasquenched by adding ammonium chloride solution (25 mL) and diluted withethyl acetate (50 mL). The mixture was acidified with hydrochloric acid(10 mL, 3N) and stirred for 15 minutes and basified with saturatedpotassium carbonate solution (20 mL). The mixture was extracted withethylacetate (3×100 mL), washed with water (2×50 mL), brine (25 mL),dried and concentrated. The crude residue was purified by combiflash(silicagel 80 g) eluting with CMA 80 in chloroform afforded pure1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (9.95 g, 46.5%) as a colorless solid; MS (ES+): 309.2 (M+23).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(7.32 g, 26.0 mmol) in N,N-dimethylformamide (157 mL, 2032 mmol) wasadded1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (8.951 g, 31.3 mmol), N-ethyl-N-isopropylpropan-2-amine (36.3 mL,208 mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 13.36 g, 28.7 mmol) at room temperature. The resulting reactionmixture was stirred at 25° C. for 16 h. The reaction mixture was dilutedwith water (1000 mL) and extracted with ethyl acetate (3×1000 mL) andwashed with water (2×500 mL), brine (300 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered, concentrated in underreduced pressure to dryness. The residue was purified by flash columnchromatography [silica gel 80 g, eluting with a (9:1) ethyl acetate:methanol mixture in hexanes 0 to 50%] to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59b) (9.42 g, 65.8%) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.52(s, 1H, D₂O exchangeable), 8.49 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.12 (t,J=1.9 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.94-7.86 (m, 1H),7.79-7.61 (m, 5H), 7.42 (ddd, J=8.8, 4.8, 2.3 Hz, 1H), 7.24-7.12 (m,2H), 5.84 (s, 1H, D₂O exchangeable), 2.47-2.29 (m, 2H), 1.02 (qt,J=13.7, 7.4 Hz, 2H), 0.59 (ddt, J=10.3, 7.0, 3.7 Hz, 1H), 0.39-0.26 (m,2H), −0.05-−0.17 (m, 2H); MS (ES+): 572.3 (M+23).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59c)

To a stirred solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59b) (8.9 g, 16.20 mmol) in methanol (300 mL) at 0° C. was addednickel(II) chloride hexahydrate (4.81 g, 20.24 mmol). To this sodiumtetrahydroborate (6.13 g, 162 mmol) was added in small portions over aperiod of 15 minutes. The reaction was stirred for 30 minutes andquenched by adding N1-(2-aminoethyl)ethane-1,2-diamine (13.43 mL, 130mmol) and stirred for 30 minutes at room temperature. The reactionmixture was concentrated to remove methanol. The reaction mixture wasdiluted water (800 mL) and stirred for 30 minutes. The solid separatedwas collected by filtration. The solid was dissolved in chloroform (500mL), washed with water (2×200 mL).

The aqueous layer was extracted with chloroform (2×200 mL). The combinedchloroform extracts were washed with brine (2×200 mL), dried andconcentrated in vacuum. The residue purified by flash columnchromatography (silicagel 120g, eluting with CMA 80 in chloroform0-100%) to afford1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59c) (4.56 g, 50.9% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.51 (s, 1H, D₂O exchangeable), 8.49 (dt, J=4.6, 1.4 Hz, 1H), 7.72(ddt, J=7.8, 5.5, 2.7 Hz, 2H), 7.63 (d, J=7.9 Hz, 1H), 7.57 (s, 1H),7.51 (s, 1H), 7.48-7.37 (m, 3H), 7.36-7.30 (m, 1H), 7.24-7.11 (m, 2H),5.83 (s, 1H, D₂O exchangeable), 3.78 (s, 2H), 3.342 (s, 2H, D₂Oexchangeable), 2.42-2.26 (m, 2H), 1.00 (ddd, J=25.9, 14.0, 7.2 Hz, 2H),0.68-0.49 (m, 1H), 0.40-0.24 (m, 2H), −0.10 (dd, J=5.5, 3.7 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.71, −124.32; MS (ES+): 554.3 (M+1);Analysis calculated for C₂₉H₂₇F₄N₅O₂(H₂O)_(0.25): C, 62.39; H, 4.96; N,12.55; Found: C, 62.09; H, 5.05; N, 12.51.

Preparation of Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60e) Step-1: (3-amino-4-fluorophenyl)(2-(benzyloxy)phenyl)methanol(60a)

To a stirred solution of 2-(benzyloxy)benzaldehyde (49b) (31.8 g, 150mmol) in tetrahydrofuran (150 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(150 mL, 150 mmol) at 0° C. over a period of 30 min. The reaction wasstirred for 14 h at room temperature and quenched with 2 N HCl (188 mL,375 mmol) over a period of 30 min, and stirred for 1 h, TLC analysis(ethyl acetate/hexanes, 3/7, v/v) shows reaction was complete. Thereaction mixture was treated with 2 N NaOH (225 mL, 450 mmol) andextracted with ethyl acetate (2×750 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography (silicagel 1 kg, eluting with 0-70% ethyl acetate in hexane) to furnish(3-amino-4-fluorophenyl)(2-(benzyloxy)phenyl)methanol (60a) (19.54 g,40% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.48 (dd, J=7.6,1.7 Hz, 1H), 7.41-7.27 (m, 5H), 7.17 (ddd, J=8.1, 7.2, 1.8 Hz, 1H),7.04-6.91 (m, 2H), 6.88-6.71 (m, 2H), 6.43 (ddd, J=8.3, 4.5, 2.1 Hz,1H), 5.90 (d, J=4.2 Hz, 1H), 5.56 (d, J=4.3 Hz, 1H, D₂O exchangeable),5.09 (s, 2H), 5.01 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −137.98; MS (ES+): MS (ES+) 346.2 (M+Na), MS (ES−) 322.1 (M−1).

Step-2: Preparation ofN-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60b)

In a 1 L single-necked flask1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(12.67 g, 45.1 mmol),(3-amino-4-fluorophenyl)(2-(benzyloxy)phenyl)methanol (60a) (12.14 g,37.5 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (21.00 g, 45.1 mmol) were treatedwith N,N-dimethylformamide (218 mL, 2816 mmol) andN-ethyl-N-isopropylpropan-2-amine (32.7 mL, 188 mmol) successively in apositive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. The residue was diluted with ethyl acetate (750mL), and layer was separated with water (2 L), aq. layer was againextracted with ethyl acetate (2×400 mL), combined organics were driedover anhydrous MgSO₄, filtered, evaporated to dryness. The residue wasthen purified by flash column chromatography [silica gel 1 kg, elutingwith ethyl acetate in hexanes from 0-100%] to furnishN-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60b) (15.16 g, 25.8 mmol, 68.8% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.17-8.09 (m, 1H), 7.99 (dt, J=7.7, 1.3Hz, 1H), 7.88 (dt, J=8.1, 1.3 Hz, 1H), 7.79-7.66 (m, 2H), 7.56-7.44 (m,2H), 7.30 (s, 5H), 7.16 (dd, J=7.4, 1.4 Hz, 3H), 7.06-6.92 (m, 2H), 5.98(d, J=4.3 Hz, 1H), 5.83 (d, J=4.3 Hz, 1H), 5.08 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.97, −123.49; MS (ES⁺): MS (ES+) 609.3 (M+Na); MS(ES+) 585.2 (M−1).

Step-3: Preparation ofN-(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60c)

To a solution ofN-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60b) (14.91 g, 25.4 mmol) in dichloromethane (120 mL) at 0° C. wasadded thionyl chloride (3.71 mL, 50.8 mmol), reaction mixture stirredfor for 6 h by maintaining 0° C. TLC analysis shows reaction wasincomplete, then added one more eq. of thionyl chloride (3.02 g, 25.4mmol) at 0° C. and stirred for 1 h. The reaction mixture was quenchedwith triethylamine (11.35 mL, 81 mmol), and solution was stirred for 30min at room temperature, and concentrated in vacuum to dryness. Theresidue was dissolved in cyclopropylmethanamine (22.05 mL, 254 mmol) andacetonitrile (120 mL) and stirred at 80° C. for 16 h, at this time TLCanalysis (ethyl acetate/hexanes, 1/1, v/v) shows maximum conversion,reaction mixture was cooled to room temperature, and evaporated todryness. The residue was purified by flash column chromatography (silicagel 1 kg, eluting with methanol in chloroform from 0-100%) to affordN-(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60c) (9.25 g, 57% yield) as a pale yellow solid. ¹HNMR (300 MHz,DMSO-d6) δ 10.50 (s, 1H), 8.15-8.10 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz,1H), 7.94-7.86 (m, 1H), 7.76-7.67 (m, 2H), 7.56-7.43 (m, 2H), 7.32 (tdd,J=7.4, 5.0, 2.3 Hz, 5H), 7.23-7.14 (m, 3H), 7.05-6.90 (m, 2H), 5.19 (s,1H), 5.08 (s, 2H), 2.24 (qd, J=12.0, 6.7 Hz, 2H), 0.85 (d, J=11.2 Hz,1H), 0.32 (dq, J=7.8, 1.7 Hz, 2H), −0.00-−0.05 (m, 2H); MS (ES+) 640.3(M+1); MS (ES+) 638.3 (M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60d)

To a solution ofN-(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60c) (7.59 g, 11.87 mmol) in dichloromethane (150 mL) cooled to −78° C.was added drop-wise under a nitrogen atmosphere tribromoborane (1 Msolution in dichloromethane) (13.05 mL, 13.05 mmol). The reactionmixture was allowed to warm to room temperature and stirred at roomtemperature 15 h. The reaction mixture was treated with methanol (3×100mL), and co-evaporated, then quenched with water (100 mL) and extractedwith chloroform (3×100 mL), combined organic layers were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue was thenpurified by flash column chromatography [silica gel 120 g, eluting withmethanol in chloroform from 0-50%] to furnish1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60d) (7.407 g) as a yellow syrup which was taken as such to the nextstep; MS (ES⁻): 548.3 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60e)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(CVR-008-141) (7.35 g, 13.38 mmol) in anhydrous methanol (120 mL),cooled to 0° C., were added and stirred for 10 min, then nickel(II)chloride hexahydrate (2.384 g, 10.03 mmol), sodium borohydride (5.06 g,134 mmol) was then added in small portions over a period of 4 h. Thereaction was exothermic and effervescent. The reaction mixture wasstirred for 45 min at 0° C., at this pointN1-(2-aminoethyl)ethane-1,2-diamine (14.45 mL, 134 mmol) was added. Themixture was allowed to stir for 1 h more before solvent was evaporated.The residue was treated with water (400 mL), and extracted withchloroform (2×300 mL) combined organic layers were dried over anhydrousMgSO₄, filtered, excess solvents were pumped-off under reduced pressure.

The residue was purified by flash column chromatography [(silica gel 120g, followed by two separate 80 g columns, eluting withmethanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60e) (0.840 g, 1.517 mmol, 11.35% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O exchangeable), 7.65-7.55 (m, 2H), 7.51(s, 1H), 7.47-7.40 (m, 2H), 7.33 (dtt, J=6.8, 4.6, 2.5 Hz, 2H),7.28-7.13 (m, 1H), 7.03 (ddt, J=8.5, 5.1, 1.7 Hz, 2H), 6.76-6.65 (m,2H), 5.03 (s, 1H), 3.78 (s, 2H), 2.45-2.37 (m, 1H), 2.25 (dd, J=12.2,7.0 Hz, 1H), 0.97-0.83 (m, 1H), 0.42-0.38 (m, 2H), 0.07 (d, J=5.1 Hz,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −123.06; MS (ES+) 554.3 (M+1),576.2 (M+Na), 552.2 (M−1), 588.2 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (61e) Step-1: Preparation of(3-amino-4-fluorophenyl)(2-methoxynaphthalen-1-yl)methanol (61a)

To a stirred solution of 2-methoxy-1-naphthaldehyde (51a) (24.21 g, 130mmol) in tetrahydrofuran (100 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(130 mL, 130 mmol) at 0° C. The reaction was stirred for 20 h at roomtemperature and quenched by adding hydrogen chloride (2N) (163 mL, 325mmol), stirred for 1 h, TLC analysis (ethyl acetate/hexanes, 3/7, v/v)shows reaction was complete. The reaction mixture was treated withsodium hydroxide (2N) (195 mL, 390 mmol) and extracted with ethylacetate (2×750 mL). The organic layers were combined dried overanhydrous MgSO₄, filtered, and evaporated to dryness. The crude residuewas purified by flash column chromatography (silica gel 1.3 kg, elutingwith 0-70% ethyl acetate in hexane) to furnish(3-amino-4-fluorophenyl)(2-methoxynaphthalen-1-yl)methanol (61a) (24.84g, 84 mmol, 64.3% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.28-8.10 (m, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.84-7.72 (m, 1H), 7.48 (d,J=9.1 Hz, 1H), 7.35-7.17 (m, 2H), 6.91-6.70 (m, 2H), 6.66-6.57 (m, 1H),6.46 (dddd, J=8.2, 4.6, 2.2, 1.0 Hz, 1H), 5.91 (d, J=4.6 Hz, 1H, D₂Oexchangeable), 4.98 (s, 2H, D₂O exchangeable), 3.96 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −139.08; MS (ES⁺): MS (ES+) 320.2 (M+Na), MS (ES−)296.0 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61b)

A 1 L single-necked flask was charged with1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(16.04 g, 57.0 mmol),(3-amino-4-fluorophenyl)(2-methoxynaphthalen-1-yl)methanol (61a) (14.13g, 47.5 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (26.6 g, 57.0 mmol) and weretreated with N,N-dimethylformamide (276 mL, 3564 mmol) andN-ethyl-N-isopropylpropan-2-amine (41.4 mL, 238 mmol) successively in apositive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. The residue was diluted with ethyl acetate (750mL), and layer was separated with water (2 L), aq. layer was againextracted with ethyl acetate (500 mL), combined organics were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue was thenpurified by flash column chromatography [silica gel 800 g, eluting withethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61b) (11.819 g, 44% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.49 (s, 1H, D₂O exchangeable), 8.20-8.08 (m, 2H), 8.00 (dt, J=7.7,1.3 Hz, 1H), 7.95-7.85 (m, 2H), 7.85-7.78 (m, 1H), 7.75-7.65 (m, 2H),7.56-7.43 (m, 2H), 7.30-7.13 (m, 4H), 6.72 (d, J=4.6 Hz, 1H), 6.19 (d,J=4.6 Hz, 1H, D₂O exchangeable), 3.97 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.98, −124.01; IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CN stretching);MS (ES⁺): MS (ES+) 583.2 (M+Na), MS (ES−) 559.2 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61c)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61b) (11.61 g, 20.71 mmol) in dichloromethane (120 mL) at 0° C. wasadded thionyl chloride (3.02 mL, 41.4 mmol), reaction mixture stirredfor for 4.5 h from 0° C. to room temperature. The reaction mixture wasquenched with triethylamine (9.25 mL, 66.3 mmol), and solution wasstirred for 30 min at room temperature, and concentrated in vacuum todryness. The residue was dissolved in cyclopropylmethanamine (14.37 mL,166 mmol) and acetonitrile (120 mL) and stirred at 80° C. for 16 h, atthis time TLC analysis (ethyl acetate/hexanes, 1/1, v/v) shows maximumconversion, reaction mixture was cooled to room temperature, andevaporated to dryness. The residue was purified by flash columnchromatography (two separate silica gel columns, size 120 g, elutingwith CMA80 in chloroform from 0-100%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61c) (10.828 g, 85% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.49 (s, 1H, D₂O exchangeable), 8.29 (d, J=8.5 Hz, 1H),8.16-8.09 (m, 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.94-7.81 (m, 3H),7.76-7.65 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.34(dt, J=14.5, 7.5 Hz, 2H), 7.27-7.10 (m, 2H), 5.87 (s, 1H), 3.85 (s, 3H),2.12 (s, 1H), 0.90 (s, 1H), 0.45-0.24 (m, 2H), 0.06-−0.14 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.97, −123.98; IR (KBr, cm⁻¹): 2234 cm⁻¹ (—CNstretching); MS (ES⁺): MS (ES+) 614.3 (M+1), MS (ES−) 612.3 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61d)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61c) (9.61 g, 15.66 mmol) in anhydrous methanol (180 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.931 g, 3.92 mmol),sodium borohydride (4.74 g, 125 mmol) was then added in small portionsover a period of 1 h. The reaction was exothermic and effervescent. Thereaction mixture was stirred for 3 h at 0° C., TLC analysis(methanol/chloroform, 9/1) shows partial (approx. 10-20%), again addednickel(II) chloride hexahydrate (0.931 g, 3.92 mmol), and NaBH₄ (1.5 g)was added in small portions over a period of 20 min, and stirred thesolution for 30 min at this point N1-(2-aminoethyl)ethane-1,2-diamine(16.92 mL, 157 mmol) was added. The mixture was allowed to stir for 4 hmore before solvent was evaporated. The residue was treated with water(200 mL), and extracted with chloroform (2×300 mL), combined organiclayers were dried over anhydrous MgSO₄, and filtered, excess solventswere pumped-off under reduced pressure. The residue was purified byflash column chromatography [(silica gel, two separate 120 g (slurry wassliced to half), eluting with methanol/chloroform from 0 to 40%)] tofurnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61d) (3.28 g, 34% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.50 (s, 1H, D₂O exchangeable), 8.29 (d, J=8.4 Hz, 1H), 7.87(dd, J=11.5, 8.1 Hz, 2H), 7.55 (t, J=9.6 Hz, 3H), 7.49 (s, 1H),7.47-7.41 (m, 2H), 7.41-7.29 (m, 3H), 7.16 (dt, J=18.7, 9.7 Hz, 2H),5.86 (s, 1H), 3.84 (s, 3H), 3.80 (s, 2H), 2.11 (dd, J=11.8, 7.3 Hz, 1H),1.02-0.79 (m, 1H), 0.34 (dq, J=8.1, 1.7 Hz, 2H), 0.10-−0.24 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.74, −124.35; MS (ES⁺): MS (ES+) 618.3(M+1), 652.3 (M+Cl).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (61e)

To a stirred solution of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61d) (0.250 g, 0.405 mmol) in anhydrous methanol (15 mL), was treatedwith 2 N HCl (in methanol) (1.012 mL, 2.024 mmol) and stirred for 10min, and evaporated to dryness to furnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidedihydrochloride (61e) (253 mg, 91% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.91 (s, 1H), 9.24 (s, 1H), 8.51 (s, 3H),8.24 (d, J=8.7 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.95 (dd, J=8.3, 1.4 Hz,1H), 7.89 (dd, J=7.4, 2.3 Hz, 1H), 7.77-7.54 (m, 5H), 7.53-7.31 (m, 4H),6.39 (t, J=6.4 Hz, 1H), 4.11 (q, J=5.9 Hz, 2H), 4.03 (s, 3H), 2.98-2.78(m, 1H), 2.72 (d, J=7.8 Hz, 1H), 1.20-1.01 (m, 1H), 0.51 (ddt, J=16.9,9.3, 4.7 Hz, 2H), 0.22 (ddt, J=17.7, 9.0, 4.8 Hz, 2H); ¹H NMR (300 MHz,DMSO-d₆ D₂O) δ 8.20 (d, J=8.8 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 7.96 (dd,J=8.3, 1.4 Hz, 1H), 7.88 (dd, J=7.3, 2.5 Hz, 1H), 7.75-7.31 (m, 10H),6.35 (s, 1H), 4.11 (s, 2H), 4.03 (s, 3H), 2.89 (dd, J=12.9, 6.9 Hz, 1H),2.72 (dd, J=12.9, 7.7 Hz, 1H), 1.08 (d, J=8.3 Hz, 1H), 0.54 (dd, J=13.1,6.3 Hz, 2H), 0.23 (ddd, J=19.1, 9.3, 5.0 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.79, −120.01; MS (ES⁺): MS (ES+) 618.3 (M+1), 616.3 (M−1),652.3 (M+Cl); Analysis calculated for: C₃₄H₃₁F₄N₅O₂.1.75H₂O.2HCl: C,56.55; H, 5.09; Cl, 9.82; N, 9.70; Found: C, 56.64; H, 5.06; Cl, 9.62;N, 9.56.

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(63a),(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(63b)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(61e) (2.0 g) was separated using Preparative SFC method. Column: 2.1×25cm ChiralPak IC SFC from Chiral Technologies; CO₂ Co-solvent (Solvent B)Acetonitrile:Isopropanol (4:1) with 1% Isopropylamine; Isocratic Method:40% Co-solvent at 80 mL/min; System pressure 100 bar; Column temperature25° C.; sample diluents methanol, to furnish:

-   -   1. Peak-1 corresponding to        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63a) (136 mg, >95% ee); This product (112 mg) was purified by        flash column chromatography (silica gel 12 kg, eluting with        0-60% methanol in chloroform) to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63a) (0.069 g, 50.7%, >95% ee) as a white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.48 (s, 1H, D₂O exchangeable), 8.29 (d, J=8.4        Hz, 1H), 7.87 (dd, J=11.9, 8.5 Hz, 2H), 7.61-7.53 (m, 2H), 7.50        (d, J=5.9 Hz, 1H), 7.47-7.28 (m, 5H), 7.19 (s, 2H), 7.17-7.09        (m, 1H), 5.86 (s, 1H), 3.84 (s, 3H), 3.78 (s, 2H), 2.13 (d,        J=8.0 Hz, 1H), 0.89 (d, J=8.5 Hz, 1H), 0.34 (dt, J=8.1, 1.9 Hz,        2H), −0.11 (dd, J=9.7, 4.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.73, −124.39; MS (ES+) 618.3 (M+1), 652.3 (M+Cl). Optical        rotation: [α]D=(−) 88.88 [CH₃OH, 0.75]; Free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        dihydrochloride (63a) (69 mg) was dissolved in methanol (15 mL)        and added 2 N HCl (0.28 mL, 5 eq.) and stirred at room        temperature for 10 min. The solution was evaporated to dryness        to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63a) (0.069 g) hydrochloride salt as an off-white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.77 (s, 1H, D₂O exchangeable), 9.89 (s,        1H, D₂O exchangeable), 9.22 (s, 1H, D₂O exchangeable), 8.49 (s,        3H, D₂O exchangeable), 8.24 (d, J=8.7 Hz, 1H), 8.08 (d, J=9.1        Hz, 1H), 7.95 (dd, J=8.3, 1.4 Hz, 1H), 7.89 (dd, J=7.5, 2.3 Hz,        1H), 7.75-7.53 (m, 7H), 7.53-7.32 (m, 4H), 6.37 (d, J=7.0 Hz,        1H), 4.11 (q, J=5.9 Hz, 2H), 4.03 (s, 3H), 2.88 (d, J=11.9 Hz,        1H), 2.72 (d, J=9.6 Hz, 1H), 1.11 (s, 1H), 0.63-0.39 (m, 2H),        0.23 (ddq, J=17.8, 9.4, 4.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −60.81, −120.03; MS (ES⁺): MS (ES+) 618.3 (M+1), MS (ES−)        652.2 (M+Cl); Analysis calculated for C₃₄H₃₁F₄N₅O₂.2H₂O.2HCl: C,        56.20; H, 5.13; Cl, 9.76; N, 9.64; Found: C, 56.64; H, 5.14; Cl,        9.35; N, 9.59.    -   2. Peak-2 corresponding to        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63b) (107 mg, >95% ee); This product (107 mg) was purified by        flash column chromatography (silica gel 12 g, eluting with 0-60%        methanol in chloroform) to furnish 83 mg of BCX-7362 free-base.        ¹H NMR (300 MHz, DMSO-d₆) δ 10.49 (s, 1H, D₂O exchangeable),        8.29 (d, J=8.5 Hz, 1H), 7.96-7.79 (m, 2H), 7.61-7.48 (m, 4H),        7.46 (s, 1H), 7.44-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.24-7.08        (m, 2H), 5.86 (s, 1H), 3.84 (s, 3H), 3.79 (s, 2H), 2.19-2.04 (m,        1H), 0.89 (q, J=6.7 Hz, 1H), 0.34 (dt, J=8.0, 2.0 Hz, 2H), −0.11        (td, J=8.8, 7.6, 4.2 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.74, −124.37; MS (ES+) 618.3 (M+1), 616.2 (M−1), 652.3        (M+Cl); Optical rotation: [α]D=(+) 103.11 [CH₃OH, 0.9]; To a        solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63b) (63 mgs) in methanol (15 mL) was added hydrogen chloride        (0.336 mL, 0.672 mmol) and stirred at room temperature for 10        min. the solution was evaporated to dryness to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (63b) hydrochloride salt (49 mgs) as an off-white solid with HCl        salt. ¹H NMR (300 MHz, DMSO-d₆) δ 10.74 (s, 1H, D₂O        exchangeable), 9.81 (s, 1H, D₂O exchangeable), 9.21 (s, 1H, D₂O        exchangeable), 8.43 (s, 3H, D₂O exchangeable), 8.24 (d, J=8.7        Hz, 1H), 8.13-8.05 (m, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.88 (d,        J=7.0 Hz, 1H), 7.75-7.54 (m, 5H), 7.53-7.32 (m, 3H), 6.39 (s,        1H), 4.11 (d, J=5.7 Hz, 2H), 4.03 (d, J=1.5 Hz, 3H), 2.87 (s,        1H), 2.72 (s, 1H), 1.10 (s, 1H), 0.50 (d, J=9.4 Hz, 2H), 0.22        (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −120.05; MS (ES⁺):        MS (ES+) 618.3 (M+1), MS (ES−) 652.2 (M+Cl). Analysis calculated        for C₃₄H₃₁F₄N₅O₂.2H₂O.2HCl: C, 56.20; H, 5.13; Cl, 9.76; N,        9.64; Found: C, 56.67; H, 5.18; Cl, 9.34; N, 9.58.

The following analytical method was used to check chiral purity ofcompounds 63a and 63b. Analytical SFC Method

Column 4.6 × 100 mm ChiralPak IC SFC from chiral technologies CO₂Co-solvent Acetonitrile:Isopropanol (4:1) with .1% (Solvent B)Isopropylamine Isocratic Method 35% Co-solvent at 4 mL/min SystemPressure 150 bar Column Temperature 40° C. Sample Diluent Methanol

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(64a) and(+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(64b)

Racemic1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53f) (660 mg) was purified by preparative chiral HPLC using CHIRALPAKAD-H, 5μ, 4.6×250 mm, flow rate 1 mL/min, Solvent: 80% Hexane/20%EtOH/0.1% DEA, UV=320 nM to furnish

-   -   1. Peak-1 corresponding to        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64a) [0.304 g, Rt=7.401 min, 99.6953% for peak-1 (64a),        Rt=9.479 0.3047% for peak-2 (64b) 99.4% ee]. This product was        purified by flash column chromatography (silica gel 25 g,        eluting 0-25% methanol in chloroform for 13 mins) to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64a) (0.270 g) as a white solid. Optical rotation −6.30 (MeOH,        1.46); ¹H NMR (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.61-7.52 (m,        4H), 7.48-7.40 (m, 2H), 7.33 (dt, J=6.4, 2.5 Hz, 1H), 7.27 (t,        J=7.8 Hz, 1H), 7.09 (dd, J=7.6, 1.6 Hz, 1H), 6.93 (t, J=7.7 Hz,        1H), 6.53 (t, J=1.9 Hz, 1H), 6.50-6.44 (m, 1H), 6.40 (ddd,        J=7.9, 2.3, 1.0 Hz, 1H), 5.23 (s, 1H), 5.06 (s, 2H), 3.80 (s,        2H), 3.20 (dd, J=6.8, 1.5 Hz, 2H), 1.05-0.98 (m, 1H), 0.51-0.41        (m, 2H), 0.19-0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71;        MS (ES+) 536.3 (M+1); (ES−) 570.3 (M+Cl). Free base        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64a) was dissolved in methanol and added (2.5 mL) of 2 N HCl in        methanol. The mixture was concentrated in vacuum to dryness to        furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64a) (270 mg) as a hydrochloride salt; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.85 (s, 1H), 9.80 (s, 3H), 8.46 (s, 3H), 7.74-7.57        (m, 6H), 7.56-7.50 (m, 2H), 7.42-7.22 (m, 4H), 7.17-7.11 (m,        2H), 5.48 (s, 1H), 4.19-4.00 (m, 2H), 3.24 (d, J=6.7 Hz, 2H),        1.15-1.00 (m, 1H), 0.57-0.40 (m, 2H), 0.17 (ddd, J=5.7, 4.7, 3.6        Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ 10.84 (s, 1H),        7.73-7.65 (m, 3H), 7.64-7.49 (m, 4H), 7.45-7.26 (m, 4H), 7.15        (dd, J=7.9, 5.2 Hz, 2H), 5.49 (s, 1H), 4.13 (s, 2H), 3.25 (d,        J=6.8 Hz, 2H), 1.14-0.95 (m, 1H), 0.58-0.38 (m, 2H), 0.29-0.05        (m, 2H); 19F NMR (282 MHz, DMSO) δ −60.77; MS (ES+) 536.3 (M+1);        (ES−) 534.3 (M−1), 570.3 (M+Cl); Chiral purity checked by chiral        HPLC using AD-H column; isocratic method 85/15/0.1        (Hexane/ethanol/TEA) 0.5 mL/min, UV 260 nM, 40 mins run time,        Temp 5° C.) [Rt=20.22 (100% peak-1 for 64a) Rt=27.323 (0%,        peak-2 for 64b, >99% ee); Analysis calculated for        C₂₉H₂₈F₃N₅O₂.2.1HCl.H₂O: C, 55.27; H, 5.13; Cl, 11.81; N, 11.11;        Found: C, 55.18; H, 5.20; Cl, 11.74; N, 10.93.    -   2. Peak-2 corresponding to        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64b) (0.308 gm) was purified by flash column chromatography        (silica gel 25 g, eluting 0-30% MeOH in chloroform for 25 min)        to afford to        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64b) (0.251 g, 92.67% ee) as free-base Optical rotation:        [α]_(D)=(+) 6.66 [CH₃OH, 1.38]. ¹H NMR (300 MHz, DMSO-d₆) δ        10.72 (s, 1H, D₂O exchangeable), 7.56 (dd, J=11.1, 7.1 Hz, 4H),        7.47-7.39 (m, 2H), 7.35-7.22 (m, 2H), 7.09 (d, J=7.7 Hz, 1H),        6.93 (t, J=7.7 Hz, 1H), 6.58-6.37 (m, 3H), 5.23 (s, 1H), 5.06        (s, 2H), 3.77 (s, 2H), 3.20 (dd, J=6.8, 1.5 Hz, 2H), 1.04 (s,        1H), 0.61-0.30 (m, 2H), 0.23-0.09 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −60.70. MS (ES+) 536.3 (M+1), 534.3 (M−1). To a        solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64b) (245 mg) in methanol (8 mL) was added 2 N HCl (in        methanol, 2.3 mL, 10 eq.) and stirred at room temperature for 30        min. The solution was evaporated to dryness to afford to        (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (64b) (239 mg, 98%) hydrochloride salt as an off-white solid; ¹H        NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H, D₂O exchangeable), 9.66        (s, 2H, D₂O exchangeable), 8.43 (s, 4H, D₂O exchangeable),        7.75-7.48 (m, 8H), 7.35 (dt, J=19.9, 7.8 Hz, 2H), 7.24 (s, 2H),        7.13 (d, J=7.7 Hz, 3H), 5.48 (s, 1H), 4.12 (s, 2H), 3.24 (d,        J=6.8 Hz, 2H), 1.16-0.98 (m, 1H), 0.59-0.36 (m, 2H), 0.17 (h,        J=3.8 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 7.71 (d, J=1.9        Hz, 1H), 7.68 (t, J=2.0 Hz, 1H), 7.65 (s, 1H), 7.61-7.55 (m,        3H), 7.52 (td, J=5.2, 2.5 Hz, 1H), 7.45-7.23 (m, 4H), 7.14 (dd,        J=6.9, 3.0 Hz, 2H), 5.48 (s, 1H), 4.13 (s, 2H), 3.25 (d, J=6.8        Hz, 2H), 1.17-0.97 (m, 1H), 0.61-0.36 (m, 2H), 0.27-0.05 (m,        2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES⁺): MS (ES+)        536.3 (M+1), 534.3 (M−1), 570.3 (M+Cl); Analysis calculated for:        C₂₉H₂₈F₃N₅O₂.1.5H₂O₂HCl: C, 54.81; H, 5.23; Cl, 11.16; N, 11.02;        Found: C, 55.01; H, 5.21; Cl, 11.05; N, 11.01; Chiral purity        checked by chiral HPLC using AD-H column; isocratic method        85/15/0.1 (Hexane/ethanol/TEA) 0.5 mL/min, UV 260 nM, 40 mins        run time, Temp 5° C.) Rt=20.427 (3.6638% peak-1 for 64a)        Rt=27.260 (96.3362%, peak-2, for 64b, 92.67% ee); Analysis        calculated for C₂₉H₂₈F₃N₅O₂.1.5H₂O.2HCl: C, 54.81; H, 5.23; Cl,        11.16; N, 11.02; Found: C, 55.01; H, 5.21; Cl, 11.05; N, 11.01.

Preparation of chiral isomer-11-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(65a) and chiral isomer-21-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(65b)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(57e) (240 mg) was separated into pure chiral isomers using preparativechiral HPLC. The condition used was as follows:

Column 3.0 × 25.0 cm RegisPack from Regis Technologies (Morton Grove,IL) Solvent Hexane:Ethanol:Diethylamine (80:20:0.1) Isocratic Method 50mL/min System Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanol

-   -   1. Peak-1 was assigned as chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (65a). The compound was repurified by flash column        chromatography (silica gel, 4 g eluting with methanol in        chloroform 0 to 25%) to afford pure chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (65a) (17 mg, 62.35% ee); 1H NMR (300 MHz, DMSO-d₆) δ 10.58 (s,        1H), 7.58 (s, 1H), 7.52 (d, J=5.7 Hz, 2H), 7.48-7.39 (m, 2H),        7.34 (d, J=7.0 Hz, 1H), 7.26-7.17 (m, 2H), 6.94 (t, J=7.7 Hz,        1H), 6.52 (t, J=2.0 Hz, 1H), 6.50-6.37 (m, 2H), 5.26 (s, 1H),        5.08 (s, 2H), 3.80 (s, 2H), 3.19 (dd, J=6.9, 3.1 Hz, 2H), 1.04        (dd, J=12.3, 6.3 Hz, 1H), 0.45 (dt, J=9.0, 2.8 Hz, 2H), 0.14 (q,        J=4.8 Hz, 2H); Mass spec (ES+) 554.3 (M+1). (ES−) 552.2 (M−1);        Chiral purity checked by chiral HPLC using chiral AD-H column;        solvent isocratic 85/15/0.1 (Hexane/ethanol/TEA); flow rate 0.8        mL/min; UV 243 nM, 25 mins run time (Temp 30° C.). Rt=18.247        (Peak-1 for 65a, 81.1746%); Rt=20.287 (peak-2 for 65b, 18.83%).    -   2. Peak-2 was assigned as chiral isomer-2        1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (65b). The compound was repurified by flash column        chromatography (silica gel, 4 g eluting with methanol in        chloroform 0 to 25%) to afford pure chiral isomer-2        1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (65b) (6 mg, 57.4% ee); ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s,        1H), 7.67-7.37 (m, 5H), 7.28-7.17 (m, 2H), 6.99-6.90 (m, 1H),        6.52 (t, J=1.9 Hz, 2H), 6.43 (dddd, J=10.3, 7.9, 2.6, 1.1 Hz,        2H), 5.25 (d, J=5.2 Hz, 1H), 5.07 (s, 2H), 3.19 (dd, J=6.7, 2.5        Hz, 2H), 1.10-0.96 (m, 1H), 0.44 (m, 2H), 0.19-0.02 (m, 2H); ¹⁹F        NMR (282 MHz, DMSO-d₆) δ −60.79, −123.04. Chiral purity checked        by chiral HPLC using chiral AD-H column; solvent isocratic        85/15/0.1 (Hexane/ethanol/TEA); flow rate 0.8 mL/min; UV 243 nM,        25 mins run time (Temp 30° C.). R_(t)=18.41 (peak-1 for 65a,        21.30%) R_(t)=20.31 (peak-2 for 65b, 78.70%).

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(66a) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(66b)

Isomers of racemic1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(60e) (335 mg) were separated using Chiral Preparative SFC. Method used;Column: 3.0×25 cm RegisPack from Regis Technologies (Morton Grove,Ill.); Solvent Hexane:ethanol (9:1) with 0.1% diethylamine; IsocraticMethod: 60 g/min; System pressure 100 bar; Column temperature 25° C.;sample diluents ethanol, to furnish:

-   -   1. Peak-1 was assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66a) (37 mg). This material was repurified by flash column        chromatography (silica gel 12 g, eluting with 0-30% methanol in        chloroform) to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66a) (2 mg, 44% ee). ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H),        7.58 (d, J=12.0 Hz, 3H), 7.52-7.19 (m, 5H), 7.10-6.96 (m, 2H),        6.78-6.62 (m, 2H), 5.03 (s, 1H), 3.87 (s, 2H), 2.44-2.32 (m,        1H), 2.31-2.19 (m, 1H), 1.00-0.82 (m, 1H), 0.46-0.33 (m, 2H),        0.15-0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77, −122.98;        MS (ES+) 554.2 (M+1).    -   2. Peak-2 was assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66b) (44 mg, 92% ee). This was repurified by flash column        chromatography (silica gel 12 g, eluting with 0-30% methanol in        chloroform) to furnish free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66b) (40 mgs); Optical rotation: [α]_(D)=(+) 61.86 [CH₃OH,        0.86]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.57 (s, 1H, D₂O        exchangeable), 7.64-7.54 (m, 2H), 7.51 (s, 1H), 7.47-7.40 (m,        2H), 7.32 (dq, J=6.8, 2.3 Hz, 2H), 7.23 (dd, J=10.3, 8.5 Hz,        1H), 7.03 (td, J=6.3, 2.4 Hz, 2H), 6.75-6.64 (m, 2H), 5.03 (s,        1H), 3.77 (s, 2H), 2.45-2.35 (m, 2H), 2.31-2.18 (m, 1H),        1.02-0.86 (m, 1H), 0.52-0.29 (m, 2H), 0.14-0.03 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.73 (d, J=5.3 Hz), −123.06; MS (ES+)        554.4 (M+1), 552.4 (M−1). To a solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66b) (29 mgs) in methanol (4 mL) added 2 N HCl (0.131 mL, 5        eq.), stirred for 30 mins and evaporated to dryness to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (66b) (20 mgs) hydrochloride salt as an off-white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.83 (s, 1H, D₂O exchangeable), 10.39 (s,        1H, D₂O exchangeable), 10.08 (s, 1H, D₂O exchangeable), 9.77 (s,        1H, D₂O exchangeable), 8.51 (d, J=7.3 Hz, 3H, D₂O exchangeable),        7.92-7.46 (m, 8H), 7.37 (dd, J=10.3, 8.5 Hz, 1H), 7.18 (td,        J=7.7, 1.6 Hz, 1H), 7.01-6.81 (m, 2H), 5.88-5.58 (m, 1H), 4.12        (q, J=5.8 Hz, 2H), 2.72 (q, J=5.9 Hz, 2H), 1.13 (ddd, J=12.9,        8.7, 3.8 Hz, 1H), 0.64-0.45 (m, 2H), 0.38-0.18 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.81, −120.50; MS (ES+) 554.3 (M+1),        552.3 (M−1), 588.3 (M+Cl); Calculated for C₂₉H₂₇F₄N₅O₂.2.1HCl        1.5H₂O: C, 53.00; H, 4.92; Cl, 11.33; N, 10.66; Found: C, 52.90;        H, 4.90; Cl, 11.46; N, 10.28.

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(67a) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(67b)

Isomers of Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(58c) (2.0 g) were separated by using preparative SFC method using thefollowing conditions to furnish:

Column 2.1 × 25 cm ChiralPak IC SFC from Chiral Technologies (WestChester, PA) CO2 Co-solvent Acetonitrile:Methanol (3:1) with 1% (SolventB) Isopropylamine Isocratic Method 35% Co-solvent at 80 mL/min SystemPressure 200 bar Column Temperature 25° C. Sample Diluent MeOH:ACN (2:1)with a small amount of DCM

-   -   1. Peak-1 assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67a) (755 mg >95 ee); Optical rotation: [α]_(D)=(−) 3.10        [CH₃OH, 2.19]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H),        8.67-8.57 (m, 1H), 8.38 (dd, J=4.8, 1.6 Hz, 1H), 7.77 (dt,        J=8.2, 2.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.57 (s, 1H), 7.51 (s,        1H), 7.47-7.38 (m, 2H), 7.37-7.27 (m, 3H), 7.25-7.15 (m, 1H),        5.80 (s, 1H), 3.77 (s, 2H), 2.33 (t, J=7.9 Hz, 2H), 1.99 (s,        2H), 1.06 (q, J=9.4, 6.3 Hz, 2H), 0.63 (t, J=7.2 Hz, 1H),        0.41-0.26 (m, 2H), −0.07 (dd, J=4.8, 1.6 Hz, 2H); To a solution        of free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67a) (700 mg) in methanol (10 mL) was added hydrochloric acid        in methanol (2 M, 6.5 mL), stirred for 30 mins and concentrated        to remove excess hydrochloric acid. The residue was dried in        vacuum to give        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67a) hydrochloride salt; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s,        1H, D₂O exchangeable), 8.85 (d, J=2.1 Hz, 1H), 8.72 (dd, J=5.4,        1.4 Hz, 1H), 8.44 (t, J=7.4 Hz, 4H, 3H D₂O exchangeable), 7.87        (dd, J=8.2, 5.4 Hz, 1H), 7.72 (t, J=8.4 Hz, 3H), 7.63 (dt,        J=7.2, 1.8 Hz, 1H), 7.59-7.47 (m, 2H), 7.40 (ddd, J=8.8, 4.5,        2.3 Hz, 1H), 7.25 (dd, J=10.2, 8.7 Hz, 1H), 6.28 (s, 1H, D₂O        exchangeable), 4.11 (q, J=5.8 Hz, 2H), 2.43 (dd, J=10.6, 5.8 Hz,        2H), 1.06 (td, J=15.4, 14.2, 6.9 Hz, 2H), 0.71-0.56 (m, 1H),        0.41-0.31 (m, 2H), −0.06 (dd, J=4.1, 1.5 Hz, 2H); ¹⁹F NMR (282        MHz, DMSO-d₆) δ −57.73-−63.18 (m), −122.87 (s); Mass spec (ES+)        554.3 (M+1); (ES−) 552.2 (M−1), 588.2 (M+Cl); Analysis        calculated for C₂₉H₂₇F₄N₅O₂.2HCl.H₂O: C, 54.10; H, 4.85; Cl,        10.87; N, 10.88; Found: C, 53.97; H, 4.88; Cl, 11.19; N, 10.65.    -   2. Peak-2 assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67b) (816 mg, 97.6% ee) as a free base; Optical rotation:        [α]_(D)=(+) 3.23 [CH₃OH, 2.04]; ¹H NMR (300 MHz, DMSO-d₆) δ        10.53 (s, 1H, D₂O exchangeable), 8.62 (dd, J=2.4, 0.9 Hz, 1H),        8.38 (dd, J=4.7, 1.6 Hz, 1H), 7.78 (dt, J=8.0, 2.1 Hz, 1H), 7.65        (dd, J=7.5, 2.4 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.47-7.38        (m, 2H), 7.32 (dddd, J=8.8, 7.9, 4.7, 1.6 Hz, 3H), 7.20 (dd,        J=10.3, 8.6 Hz, 1H), 5.80 (s, 1H, D₂O exchangeable), 3.77 (s,        2H), 2.34 (t, J=7.8 Hz, 2H), 1.17-0.99 (m, J=6.8 Hz, 2H), 0.61        (dt, J=12.8, 6.9 Hz, 1H), 0.41-0.25 (m, 2H), −0.07 (dd, J=4.8,        1.6 Hz, 2H); MS (ES+) 554.3 (M+1), 576.3 (M+Na); 552.3 (M−1),        588.2 (M+Cl). To a solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67b) (700 mg) in methanol (10 mL) was added hydrochloric acid        in methanol (2 M, 6.5 mL), stirred for 30 mins and concentrated        in vacuum to remove excess hydrochloric acid. The residue was        dried to give        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (67b) (730 mg) hydrochloride salt as a white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.70 (s, 1H, D₂O exchangeable), 8.86 (s, 1H),        8.73 (d, J=5.0 Hz, 1H), 8.45 (d, J=9.5 Hz, 4H, 3H D₂O        exchangeable), 7.99-7.84 (m, 1H), 7.71 (d, J=10.0 Hz, 3H), 7.63        (d, J=7.0 Hz, 1H), 7.59-7.47 (m, 2H), 7.45-7.36 (m, 1H), 7.26        (dd, J=10.2, 8.6 Hz, 1H), 6.30 (s, 1H, D₂O exchangeable), 4.11        (q, J=5.8 Hz, 2H), 2.43 (t, J=8.5 Hz, 2H), 1.06 (dq, J=13.8,        7.8, 6.7 Hz, 2H), 0.70-0.56 (m, 1H), 0.40-0.29 (m, 2H),        −0.02-−0.09 (m, 2H); Mass spec (ES+) 554.3 (M+1), (ES−) 552.1        (M−1), 588.2 (M+Cl); Analysis calculated for        C₂₉H₂₇F₄N₅O₂.2HCl.H₂O): C, 54.10; H, 4.85; Cl, 10.87; N, 10.88;        Found: C, 53.94; H, 5.00; Cl, 11.09; N, 10.74.

Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68c),(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68d) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68e) Step-1: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (68a)

To a stirred solution of 3-cyclopropyl-1-phenylpropan-1-one (46d) (12 g,68.9 mmol) in tetrahydrofuran (10 mL) was added was added freshlyprepared (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide(52c) (88 mL, 79 mmol, 0.9 M solution in THF) at 0° C. The reaction wasallowed to stir for 2 h at 0° C., quenched with saturated aqueousammonium chloride solution (100 mL), stirred for 2 h and extracted withethyl acetate (2×100 mL). The organic layers were combined, washed withwater (2×100 mL), brine (100 mL), dried, filtered and concentrated invacuum. The crude residue was purified by flash column chromatography(silica gel, 120 g, eluting with ethyl acetate in hexanes 0-100%) toafford 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropan-1-ol(68a) (15.6 mg, 79%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.42-7.35(m, 2H), 7.25 (ddd, J=7.7, 6.9, 1.2 Hz, 2H), 7.17-7.09 (m, 1H),6.92-6.77 (m, 2H), 6.54 (ddd, J=8.5, 4.5, 2.3 Hz, 1H), 5.29 (s, 1H),4.99 (s, 2H), 2.31-2.17 (m, 2H), 1.14-0.95 (m, 2H), 0.72-0.53 (m, 1H),0.39-0.27 (m, 2H), −0.09 (td, J=5.3, 3.7 Hz, 2H).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(12.32 g, 43.8 mmol) in N,N-dimethylformamide (265 mL) was added1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (68a) (15g, 52.6 mmol), N-ethyl-N-isopropylpropan-2-amine (61.0 mL, 350 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 22.46 g,48.2 mmol) at room temperature. The reaction mixture was stirred at 25°C. for 16 h quenched with water (200 mL) and extracted with ethylacetate (3×300 mL). The organic layers were combined washed with water(2×100 mL), brine (100 mL), dried over anhydrous MgSO₄, filtered, andconcentrated in under reduced pressure to dryness. The residue waspurified by flash column chromatography (silica gel 120 g, eluting withhexanes in ethyl acetate/hexanes from 0-40 to 100%) to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68b) (18.715 g, 34.1 mmol, 78% yield); ¹H NMR (300 MHz, DMSO-d₆) δ10.52 (s, 1H, D₂O exchangeable), 8.12 (t, J=2.0 Hz, 1H), 8.00 (dt,J=7.8, 1.3 Hz, 1H), 7.96-7.85 (m, 1H), 7.78-7.67 (m, 2H), 7.57 (dd,J=7.6, 2.3 Hz, 1H), 7.44-7.37 (m, 2H), 7.35-7.23 (m, 3H), 7.21-7.16 (m,1H), 7.16-7.11 (m, 1H), 5.57 (s, 1H, D₂O exchangeable), 2.35-2.24 (m,2H), 1.06 (q, J=7.1 Hz, 2H), 0.60 (dt, J=12.1, 7.2 Hz, 1H), 0.40-0.27(m, 2H), −0.09 (td, J=5.2, 3.6 Hz, 2H).

Step-3: Preparation of Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68c)

To a stirred solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68b) (10 g, 18.23 mmol) in methanol (300 mL) at 0° C. was addednickel(II) chloride hexahydrate (1.083 g, 4.56 mmol) followed by sodiumtetrahydroborate (6.90 g, 182 mmol) in small portions over a period of15 mins. The reaction was stirred for 15 mins, quenched by addingN1-(2-aminoethyl)ethane-1,2-diamine (4.73 mL, 45.6 mmol), stirred foradditional 30 mins at room temperature and concentrated in vacuum toremove methanol. The reaction mixture was diluted water (500 mL) andstirred for 2 h. The solid separated was collected by filtration. Thesolid was dissolved in dichloromethane (500 mL) washed with water (2×200mL) extracted with dichloromethane (2×200 mL). The chloroform layerswere combined washed with brine (2×200 mL), dried and concentrated invacuum. The residue was purified by flash column chromatography (silicagel, 120 g, eluting with CMA 80 in chloroform 0-100%) to afford Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68c) (6.1 g, 11.04 mmol, 60.6% yield) as a colorless solid.

Step-4: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68d) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68e)

Isomers of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(68c) (240 mg) were separated by using preparative SFC method using thefollowing conditions to furnish: Preparative SFC Method

Column 2.1 × 25 cm ChiralPak IC SFC from Chiral Technologies (WestChester, PA) CO₂ Co-solvent Methanol w/1% Isopropylamine (Solvent B)Isocratic Method 25% Co-solvent at 80 mL/min System Pressure 100 barColumn Temperature 25° C. Sample Diluent MeOH:Dichloromethane (3:1)

-   -   1. Peak-1 assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (68d) (59 mg >95 ee); Optical rotation: [α]_(D)=(−) 0.987        [CH₃OH, 0.081]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.52 (s, 1H), 7.62        (dd, J=7.5, 2.4 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.46-7.38        (m, 4H), 7.29 (dt, J=15.0, 7.6 Hz, 4H), 7.21-7.11 (m, 2H), 5.57        (s, 1H), 3.77 (s, 2H), 2.28 (d, J=8.2 Hz, 2H), 1.05 (dd, J=10.4,        5.9 Hz, 2H), 0.62 (dq, J=12.5, 6.0, 5.4 Hz, 1H), 0.41-0.28 (m,        2H), −0.09 (t, J=4.7 Hz, 2H); 1⁹F NMR (282 MHz, DMSO-d₆) δ        −60.71, −124.35-−124.46 (m); MS (ES+) 553.3 (M+1) 575.3 (M+Na),        (ES−) 551.2 (M−1); Analysis calculated for C₃₀H₂₈F₄N₄O2: C,        65.19; H, 5.11; N, 10.14; Found: C, 65.33; H, 5.37; N, 9.88.    -   2. Peak-2 assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (68e) (124 mg >95 ee); This compound was repurified by flash        column chromatography (silica gel 12 g, eluting with CMA 80 in        chloroform) to afford pure as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (68e) (77 mg) as a white solid; Optical rotation: [α]_(D)=(+)        1.558 [CH₃OH, 0.77]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.52 (s, 1H),        7.62 (dd, J=7.5, 2.3 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H),        7.45-7.38 (m, 4H), 7.35-7.30 (m, 1H), 7.29 (d, J=2.6 Hz, 1H),        7.26 (d, J=7.7 Hz, 2H), 7.20-7.12 (m, 2H), 5.57 (s, 1H), 3.78        (s, 2H), 2.29 (t, J=8.1 Hz, 2H), 1.11-1.02 (m, 2H), 0.69-0.54        (m, 1H), 0.33 (dt, J=8.5, 2.8 Hz, 2H), −0.08 (q, J=4.8 Hz, 2H);        MS (ES+) 553.3 (M+1), (ES−) 551.2 (M−1).

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(69a) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(69b)

Isomers of Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(59c) (2.0 g) were separated by using preparative SFC method using thefollowing conditions to furnish:

Preparative SFC Method Used:

Column 2.1 × 25 cm ChiralPak IC SFC from Chiral Technologies (WestChester, PA) CO₂ Co-solvent Dichloromethane:Methanol (9:1) with 1%(Solvent B) Isopropylamine Isocratic Method 60% Co-solvent at 80 mL/minSystem Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanolChiral Purity of peaks was determined by following Analytical SFCMethod:

Column 4.6 × 100 mm ChiralPak IC SFC from Chiral Technologies (WestChester, PA) CO₂ Co-solvent Dichloromethane: Methanol (9:1) with 0.1%(Solvent B) Isopropylamine Gradient Method 5-65% Co-solvent at 4 mL/minSystem Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanol Peak-1 (69a) Rt = 2.8 min 265 mg >95% ee 95.3% purity (UV 254)(UV 254) Peak-2 (69b) Rt = 3.7 min 464 mg >95% ee 98.0% purity (UV 254)(UV 254)

-   -   1. Peak-1 assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (69a) (265 mg >95 ee) free base as a white solid. Optical        rotation: [α]_(D)=(−) 0.95 [CH₃OH, 2.105]; 1H NMR (300 MHz,        DMSO-d₆) δ 10.54 (s, 1H), 8.67-8.57 (m, 1H), 8.38 (dd, J=4.8,        1.6 ¹HNMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable),        8.52-8.46 (m, 1H), 7.77-7.68 (m, 2H), 7.61 (t, J=8.2 Hz, 3H),        7.50-7.46 (m, 2H), 7.40 (ddd, J=7.4, 5.0, 2.2 Hz, 2H), 7.23-7.12        (m, 2H), 5.83 (s, 1H, D₂O exchangeable), 5.00 (s, 2H, D₂O        exchangeable), 3.91 (s, 2H), 2.42-2.22 (m, 2H), 1.01 (s, 2H),        0.67-0.51 (m, 1H), 0.37-0.27 (m, 2H), −0.10 (p, J=4.8 Hz, 2H);        MS (ES+) 554.3 (M+1), 576.3 (M+Na); (ES−) 552.3 (M−1), 588.3        (M+Cl). To a solution of free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (69a) (250 mg) in methanol (10 mL) was added hydrochloric acid        in methanol (2 M, 2.305 mL) stirred for 30 mins and concentrated        in vacuum to remove excess hydrochloric acid. The residue was        dried to give        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (69d) (250 mg, 87% yield) hydrochloride as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.69 (s, 1H, D₂O exchangeable), 8.60 (d,        J=5.3 Hz, 1H), 8.46 (s, 3H, D₂O exchangeable), 8.11 (s, 1H),        7.89 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H),        7.70 (s, 1H), 7.63 (dt, J=7.2, 1.7 Hz, 1H), 7.59-7.42 (m, 4H),        7.23 (t, J=9.5 Hz, 1H), 4.11 (q, J=5.8 Hz, 2H), 2.47-2.35 (m,        2H), 1.20-1.04 (m, 1H), 1.04-0.86 (m, 1H), 0.60 (q, J=7.3, 6.8        Hz, 1H), 0.33 (dt, J=8.4, 2.8 Hz, 2H), −0.07 (d, J=4.5 Hz, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −123.19; MS (ES+) 554.3        (M+10), (ES−) 552.2 (M−1), 588.3 (M+Cl). Analysis calculated for        C₂₉H₂₇F₄N₅O₂.2HCl 1.75H₂O: C, 52.99; H, 4.98; Cl, 10.65; N,        10.66; Found: C, 53.07; H, 5.06; Cl, 10.88; N, 10.45.    -   2. Peak-2 assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (69e) (464 mg 90% ee) was purified by flash column        chromatography (silica gel 12 g, eluting 0-30% MeOH in        chloroform for 15 min) to afford 345 mg of (69e) as freebase        isolated. ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O        exchangeable), 8.54-8.45 (m, 1H), 7.77-7.68 (m, 2H), 7.67-7.61        (m, 3H), 7.59-7.52 (m, 1H), 7.51-7.37 (m, 3H), 7.25-7.11 (m,        2H), 5.84 (s, 1H, D₂O exchangeable), 4.01 (s, 2H), 2.44-2.27 (m,        2H), 1.02 (s, 2H), 0.68-0.50 (m, 1H), 0.41-0.23 (m, 2H), −0.11        (q, J=4.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78, −124.06;        MS (ES⁺): MS (ES+) 554.3 (M+1), MS (ES−) 552.2 (M−1), 588.2        (M+Cl); Optical rotation: [α]_(D)=(+) 1.81 [CH₃OH, 1.1]. To a        stirred solution of 69e (303 mg) in methanol (10 mL) to this 2 N        HCl (2.74 mL, 5.47 mmol) was added and stirred for 10 min and        evaporated to dryness to        (S)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (69e) (0.269 g, 89% yield) as an off-white solid as HCl salt; ¹H        NMR (300 MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.73-8.44 (m, 4H), 8.24        (s, 1H), 7.99 (s, 1H), 7.87-7.43 (m, 8H), 7.25 (dd, J=10.2, 8.7        Hz, 1H), 4.11 (q, J=5.8 Hz, 2H), 2.50 (d, J=1.9 Hz, 2H), 1.14        (s, 1H), 0.95 (td, J=12.5, 6.0 Hz, 1H), 0.72-0.53 (m, 1H), 0.33        (dt, J=8.4, 2.7 Hz, 2H), −0.06 (h, J=3.6 Hz, 2H); 1H NMR (300        MHz, DMSO-d₆, D₂O) δ 8.65 (dd, J=5.5, 1.6 Hz, 1H), 8.33 (td,        J=7.9, 1.7 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.83-7.68 (m, 3H),        7.65-7.57 (m, 3H), 7.56-7.44 (m, 2H), 7.35-7.22 (m, 1H), 4.12        (s, 2H), 2.54-2.40 (m, 2H), 1.16 (ddd, J=17.6, 14.4, 8.1 Hz,        1H), 0.96 (tt, J=12.5, 5.7 Hz, 1H), 0.63 (td, J=7.6, 4.0 Hz,        1H), 0.36 (ddt, J=8.6, 5.6, 2.8 Hz, 2H), −0.05 (dd, J=5.7, 3.7        Hz, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.80, −122.61; MS (ES⁺):        MS (ES+) 554.3 (M+1), MS (ES−) 552.3 (M−1), 588.2 (M+Cl); HPLC:        Chiral Purity 90% ee; Chiral HPLC: AD-H column 90/10/0.2        (Hexane/ethanol/TEA) 0.8 mL/min UV 260 nM, 45 mins run time        (Temp 40° C.). Rt=16.88 (Peak-1, 95.03%); Rt=19.99 (peak-2        4.96%) 90% ee; Reverse phase HPLC Rt=6.97 (95.01%); Analysis        calculated for C₂₉H₂₇F₄N₅O₂.2HCl.2H₂O: C, 52.57; H, 5.02; Cl,        10.70; N, 10.57; Found; C, 52.95; H, 5.01; Cl, 10.85; N, 10.50.

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(70a) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(70b)

Isomers of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(54e) (0.4 g) were separated by using preparative SFC method using thefollowing conditions to furnish:

Preparative SFC Method Used:

Column 20 mm × 25.0 cm ChromegaChiral CCS from Regis Technologies(Morton Grove, IL) CO₂ Co-solvent Methanol:Isopropanol (1:1) with 1%(Solvent B) Isopropylamine Isocratic Method 20% Co-solvent at80 mL/minSystem Pressure 200 bar Column Temperature 25° C. Sample DiluentMethanol:IsopropanolChiral Purity of peaks was determined by following Analytical SFCMethod:

Column 4.6 × 100 mm ChiralPak AS from Chiral Technologies (West Chester,PA) CO₂ Co-solvent Methanol:Isopropanol (1:1) with 0.1% (Solvent B)Isopropylamine Isocratic Method 5-65% Co-solvent Gradient at 4 mL/minSystem Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanol Peak-1 (70a) 2.1 min 144 mg >95% ee 98.6% purity (UV 254) (UV254) Peak-2 (70b) 2.4 min 172 mg 95.5% ee 96.5% purity (UV 254) (UV 254)

-   -   1. Peak-1 assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70a) (144 mg, >95% ee) free base as white solid; Optical        rotation: [α]_(D)=(+) 6.83 [CH₃OH, 1.2]; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.53 (s, 1H, D₂O exchangeable), 7.88 (t, J=1.7 Hz,        1H), 7.77-7.71 (m, 1H), 7.67 (dt, J=7.7, 1.4 Hz, 1H), 7.63 (dd,        J=7.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.54-7.47 (m, 2H), 7.47-7.38        (m, 2H), 7.34 (ddt, J=8.6, 5.9, 2.8 Hz, 2H), 7.22 (dd, J=10.3,        8.5 Hz, 1H), 4.93 (s, 1H), 3.77 (s, 2H), 2.31-2.21 (m, 2H),        0.97-0.80 (m, 1H), 0.42-0.33 (m, 2H), 0.10-−0.02 (m, 2H); ¹⁹F        NMR (282 MHz, DMSO-d₆) δ −60.73, −123.20; MS (ES+) 563.3 (M+1),        561.3 (M−1). To a solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70a) (120 mg) in methanol (15 mL) was added hydrogen chloride        (0.969 mL, 1.938 mmol), stirred at room temperature for 10 min,        evaporated to dryness to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70a) (100 mg) hydrochloride salt as white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.84 (s, 1H, D₂O exchangeable), 10.44 (s, 2H,        D₂O exchangeable), 8.44 (s, 3H, D₂O exchangeable), 8.30 (s, 1H,        D₂O exchangeable), 8.09 (d, J=7.9 Hz, 1H), 7.99 (d, J=6.8 Hz,        1H), 7.91-7.83 (m, 1H), 7.80-7.50 (m, 7H), 7.42 (dd, J=10.3, 8.6        Hz, 1H), 5.78 (d, J=6.9 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H),        2.88-2.62 (m, 2H), 1.42-0.99 (m, 1H), 0.73-0.46 (m, 2H), 0.32        (d, J=4.4 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −119.99;        MS (ES+): MS (ES+) 563.3 (M+1), MS (ES−) 561.3 (M−1), 597.3        (M+Cl); Analysis calculated for C₃₀H₂₆F₄N₆O.2HCl.1.75H₂O: C,        54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83;        Cl, 10.10; N, 11.97.    -   2. Peak-2 assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70b) (172 mg, 95.5% ee) as free base was repurified by flash        column chromatography (silica gel 12 g, eluting 0-30% MeOH in        chloroform for 15 min) to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70b) free base as an off-white solid; Optical rotation:        [α]_(D)=(−) 5.44 [CH₃OH, 1.25]; ¹H NMR (300 MHz, DMSO-d₆) δ 7.88        (t, J=1.6 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.70-7.61 (m, 2H),        7.57 (s, 1H), 7.54-7.47 (m, 2H), 7.45-7.41 (m, 2H), 7.34 (ddq,        J=8.7, 6.1, 3.5, 2.8 Hz, 2H), 7.22 (dd, J=10.3, 8.5 Hz, 1H),        4.93 (s, 1H), 3.78 (s, 2H), 2.25 (d, J=6.9 Hz, 2H), 0.90 (ddd,        J=9.8, 8.0, 5.2 Hz, 1H), 0.47-0.29 (m, 2H), 0.04 (dd, J=5.0, 1.5        Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73, −123.19; MS (ES+)        563.3 (M+1), MS (ES−), 561.3 (M−1). To a solution of free base        of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70b) (0.124 g, 0.220 mmol) in methanol (15 mL) was added        hydrogen chloride (1.102 mL, 2.204 mmol), stirred at room        temperature for 10 min, evaporated to dryness to afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (70b) (0.121 g) hydrochloride salt as an off-white solid; ¹H        NMR: ¹H NMR (300 MHz, DMSO-d₆) δ 10.82 (s, 1H, D₂O        exchangeable), 10.36 (s, 2H, D₂O exchangeable), 8.38 (s, 3H, D₂O        exchangeable), 8.27 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (d,        J=6.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.78-7.49 (m, 7H),        7.48-7.37 (m, 1H), 5.78 (s, 1H), 4.13 (d, J=5.7 Hz, 2H), 2.72        (s, 2H), 1.14 (s, 1H), 0.56 (d, J=7.7 Hz, 2H), 0.31 (d, J=5.0        Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82, −120.03; MS (ES⁺):        MS (ES+) 563.3 (M+1), MS (ES−), 561.3 (M−1), 597.2 (M+Cl);        Analysis calculated for C₃₀H₂₆F₄N₆O.2HCl.1.75H₂O: C, 54.02; H,        4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10;        N, 11.97.

Preparation of chiral isomer-11-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(71a) and chiral isomer-21-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(71b)

Isomers of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(52h) (235 mg) were separated into pure chiral isomers using preparativeSFC method using the following conditions to furnish:

Preparative SFC Method:

Column 20 mm × 25.0 cm Chromega Chiral CCS from Regis Technologies(Morton Grove, IL) CO₂ Co-solvent Methanol:Isopropanol (1:1) with 1%(Solvent B) Isopropylamine Isocratic Method 20% Co-solvent at 80 mL/minSystem Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanol

Chiral Purity of Peaks was Determined by Following Analytical SFCMethod:

Column 4.6 × 100 mm ChiralPak AS from Chiral Technologies (West Chester,PA) CO₂ Co-solvent Methanol:Isopropanol (1:1) with 0.1% (Solvent B)Isopropylamine Isocratic Method 5-65% Co-solvent Gradient at 4 mL/minSystem Pressure 100 bar Column Temperature 25° C. Sample DiluentMethanol Peak-1 (71a) 2.2 min 46 mg >95% ee 81.9% purity (UV 254) (UV254) Peak-2 (71b) 2.4 min 57 mg 97.7% ee 98.5% purity (UV 254) (UV 254)

-   -   1. Peak-1 assigned as chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71a) (46 mg >95 ee) was repurified by flash column        chromatography (silica gel 4 g, eluting with CMA 80 in        chloroform 0 to 30%) to afford pure chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71a) (34 mg) free base as white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 7.77 (d, J=7.3 Hz, 2H), 7.66-7.56 (m, 4H), 7.56 (s,        1H), 7.51 (s, 1H), 7.49-7.38 (m, 2H), 7.37-7.27 (m, 3H), 7.21        (dd, J=10.2, 8.5 Hz, 1H), 4.95 (s, 1H), 3.77 (s, 2H), 2.25 (d,        J=6.7 Hz, 3H), 0.95-0.84 (m, 1H), 0.43-0.30 (m, 2H), 0.10-−0.01        (m, 1H); MS (ES+) 563.3 (M+1), (ES−) 561.3 (M−1). To a solution        of free base of chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71a) (34 mgs) in methanol (2 mL) and added hydrochloric acid in        methanol (2 M 0.3 mL), stirred for 15 mins and concentrated to        remove excess hydrochloric acid. The residue was dried to give        chiral isomer-1        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71a) hydrochloride salt as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.84 (s, 1H), 10.49 (s, 2H), 8.47 (s, 3H), 8.04-7.90        (m, 5H), 7.82-7.68 (m, 3H), 7.63 (dt, J=7.4, 1.7 Hz, 1H),        7.60-7.49 (m, 2H), 7.41 (dd, J=10.2, 8.6 Hz, 1H), 5.83 (t, J=6.6        Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 2.71 (q, J=6.0, 4.6 Hz, 2H),        1.18 (td, J=13.9, 12.8, 7.3 Hz, 1H), 0.55 (dt, J=8.3, 3.1 Hz,        2H), 0.32 (t, J=5.0 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −60.81, −120.01; Analysis calculated for        C₃₀H₂₆F₄N₆O.2HCl.2.75H₂O: C, 52.65; H, 4.93; Cl, 10.22; N,        12.28; Found: C, 52.95; H, 4.87; Cl, 11.61; N, 10.06.    -   2. Peak-2 assigned as chiral isomer-2        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71b) (57 mg, 97.7% ee) free base as white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.54 (s, 1H), 7.80-7.74 (m, 2H), 7.61 (d, J=7.8        Hz, 3H), 7.57 (s, 1H), 7.52 (s, 1H), 7.43 (d, J=6.9 Hz, 2H),        7.35-7.30 (m, 2H), 7.22 (t, J=9.5 Hz, 1H), 4.95 (s, 1H), 3.79        (s, 2H), 2.25 (d, J=7.0 Hz, 2H), 0.90 (s, 1H), 0.41-0.33 (m,        2H). To a solution of free base of chiral isomer-2        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71b) in methanol (2 mL) was added hydrochloric acid in methanol        (2 M, 0.5 mL), stirred for 15 mins and concentrated in vacuum to        remove excess hydrochloric acid. The residue was dried to give        chiral isomer-2        1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (71b) (50 mgs) hydrochloride salt as a white solid; 1H NMR (300        MHz, DMSO-d₆) δ 10.83 (d, J=5.2 Hz, 1H, D₂O exchangeable), 10.45        (s, 2H, D₂O exchangeable), 8.45 (s, 3H, D₂O exchangeable),        8.04-7.89 (m, 5H), 7.81-7.67 (m, 3H), 7.66-7.60 (m, 1H),        7.59-7.48 (m, 2H), 7.47-7.36 (m, 2H), 5.81 (d, J=6.8 Hz, 1H),        4.13 (q, J=5.7 Hz, 2H), 2.71 (q, J=6.2, 5.2 Hz, 2H), 1.15 (td,        J=8.1, 5.2 Hz, 1H), 0.64-0.49 (m, 2H), 0.32 (t, J=5.0 Hz, 2H);        19F NMR (282 MHz, DMSO-d₆) δ −60.79, −120.01; MS (ES+) 563.3        (M+1), 585.3 (M+Na), 561.3 (M−1), 597.3 (M+Cl); Analysis        calculated for C₃₀H₂₆F₄N₆O.1.95HCl.1.75H₂O: C, 53.80; H, 4.81;        Cl, 10.32; N, 12.55; Found: C, 54.09; H, 4.94; Cl, 10.13; N,        11.42.

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(72c) and(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(72d)

Isomers of Racemic tert-butyl3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(56b) (0.75 gm) were separated by preparative Chiral HPLC using thefollowing preparative chromatography conditions to furnish:

Column CHIRALPAK AD-H; 5μ, 4.6 × 250 mm, flow rate 1 mL/min EluentHexane:Ethanol-Diethylamine (90:10:0.1) Column Temperature Roomtemperature UV detection 270 nm Peak-1 (72a)  8.849 min 239 mg  >99% eePeak-2 (72b) 11.589 min 220 mg 98.0% ee

-   -   1. Peak-1 assigned as (−)-tert-butyl        3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (72a) (239 mg >99% ee); Optical rotation: [α]_(D)=(−) 17.11        [CH₃OH, 0.83]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.82        (s, 1H), 7.74 (dt, J=7.5, 1.4 Hz, 1H), 7.70-7.65 (m, 1H),        7.64-7.23 (m, 10H), 5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.24        (d, J=6.8 Hz, 2H), 1.37 (s, 9H), 1.11-0.95 (m, 1H), 0.52-0.40        (m, 2H), 0.18-0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82,        −122.29; (ES+) 686.3 (M+23). To a solution of (−)-tert-butyl        3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (72a) (230 mg, 0.347 mmol) in methanol (25 mL) was added conc.        hydrogen chloride (0.180 mL, 2.156 mmol) and stirred at room        temperature for 19 h, (˜20% conversion by TLC). The reaction        mixture was concentrated under vacuum to dryness (at <30° C.,        −50% conversion by TLC). To the residue was added conc. HCl        (0.15 mL, 1.8 mmol) stirred at room temperature for 0.5 h and        concentrated in vacuum to dryness. The residue obtained was        purified by flash column chromatography [silica gel 4 g, eluting        with chloroform/CMA80 (1:0 to 3:1)] to afford free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72c) (95 mg) as a white solid; Optical rotation: [α]_(D)=(−)        15.92 [CH₃OH, 0.515]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H),        7.81 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7.6, 1.5 Hz, 1H), 7.67 (dt,        J=8.1, 1.5 Hz, 1H), 7.63-7.50 (m, 4H), 7.43 (q, J=1.5 Hz, 1H),        7.40 (d, J=7.6 Hz, 1H), 7.35-7.22 (m, 3H), 5.59 (s, 1H), 3.77        (s, 2H), 3.23 (d, J=6.8 Hz, 2H), 1.14-0.95 (m, 1H), 0.59-0.34        (m, 2H), 0.26-0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75,        −122.42; MS (ES+) 564.2 (M+1); (ES−) 562.1 (M−1). To a solution        of free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72c) (70 mg) in methanol (10 mL) was added 4 N HCl (aq. 0.12        mL) and concentrated in vacuum to dryness to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72c) (78 mg) hydrochloride salt as a white solid; Optical        rotation: [α]_(D)=(−) 9.72 [CH₃OH, 0.535]; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.49 (s, 1H), 8.08 (s, 3H), 7.66 (t, J=1.7 Hz, 1H),        7.59 (dt, J=7.6, 1.5 Hz, 1H), 7.56-7.50 (m, 3H), 7.46-7.32 (m,        5H), 7.19-7.06 (m, 2H), 5.43 (s, 1H), 3.96 (s, 2H), 3.08 (d,        J=6.8 Hz, 2H), 0.97-0.80 (m, 1H), 0.37-0.22 (m, 2H), 0.02 to        −0.04 (m, 2H). 19F NMR (282 MHz, DMSO-d₆) δ −60.83, −121.94; MS        (ES+): 564.2 (M+1); Analysis calculated for        C₃₀H₂₅F₄N₅O₂.1.15HCl.1.25H₂O: C, 57.38; H, 4.60; Cl, 6.49; N,        11.15; Found C, 57.01; H, 4.63; Cl, 6.11; N, 10.82.    -   2. Peak-2 assigned as (+)-tert-butyl        3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (72b) (220 mg, 98.0% ee); Optical rotation: [α]_(D)=(+) 17.14        [CH₃OH, 0.70]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.82        (s, 1H), 7.74 (dt, J=7.6, 1.5 Hz, 1H), 7.70-7.65 (m, 1H),        7.65-7.22 (m, 10H), 5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.24        (d, J=6.8 Hz, 2H), 1.37 (s, 9H), 1.14-0.90 (m, 1H), 0.54-0.38        (m, 2H), 0.18-0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82,        −122.34; (ES+) 686.3 (M+23). To a solution of (+)-tert-butyl        3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (72b) (210 mg, 0.316 mmol) in methanol (23 mL) was added conc.        hydrogen chloride (0.160 mL, 1.914 mmol) and stirred at room        temperature for 19 h, (˜20% conversion by TLC). The reaction        mixture was concentrated under vacuum to dryness (at <30° C.,        ˜50% conversion by TLC). To the residue was added conc. HCl        (0.13 mL, 1.56 mmol) stirred at room temperature for 10 min and        concentrated in vacuum to dryness. The residue obtained was        purified by flash column chromatography [silica gel 4 g, eluting        with chloroform/CMA80 (1:0 to 3:1)] to afford free base        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72d) (88 mg) as a white solid; Optical rotation: [α]_(D)=(+)        19.59 [CH₃OH, 0.515]; ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H),        7.82 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7.6, 1.5 Hz, 1H), 7.67 (dt,        J=8.0, 1.5 Hz, 1H), 7.63-7.50 (m, 4H), 7.44 (q, J=1.4 Hz, 1H),        7.40 (d, J=7.5 Hz, 1H), 7.36-7.22 (m, 3H), 5.59 (s, 1H), 3.78        (s, 2H), 3.23 (d, J=6.8 Hz, 2H), 1.12-0.96 (m, 1H), 0.56-0.36        (m, 2H), 0.24-0.07 (m, 2H); ¹⁹F NMR (282 MHz, DMSO d₆) δ −60.76,        −122.38; MS (ES+) 564.2 (M+1); (ES−) 562.2 (M−1); To a solution        of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72d) (62 mg) in methanol (10 mL) was added 4 N HCl (aq. 0.11        mL) and concentrated in vacuum to dryness to        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (72d) (68 mg) hydrochloride salt as a white solid; Optical        rotation: [α]_(D)=(+) 8.0 [CH₃OH, 0.325]; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.66 (s, 1H), 8.29 (s, 3H), 7.81 (t, J=1.7 Hz, 1H),        7.77-7.64 (m, 4H), 7.59 (t, J=4.7 Hz, 3H), 7.55 (d, J=4.5 Hz,        1H), 7.54-7.46 (m, 1H), 7.30 (dd, J=4.7, 2.5 Hz, 1H), 7.25 (d,        J=8.6 Hz, 1H), 5.59 (s, 1H), 4.12 (s, 2H), 3.23 (d, J=6.8 Hz,        2H), 1.13-0.96 (m, 1H), 0.55-0.36 (m, 2H), 0.26-0.03 (m, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.85, −122.03; MS (ES+) 564.2        (M+1); (ES−) 562.2 (M−1); Calculated for        C₃₀H₂₅F₄N₅O₂HCl.1.25H₂O: C, 57.88; H, 4.61; Cl, 5.70; N, 11.25;        Found C, 57.80; H, 4.57; Cl, 5.94; N, 11.05.

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(73a) and(−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(73b)

Isomers of Racemic1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(55b) (400 mg) were separated into pure chiral isomers using preparativeSFC method using the following method to furnish:

Preparative SFC Method Used:

Column 3.0 × 25.0 cm CCS from ES Industries (West Berlin, NJ) CO2Co-solvent (Solvent B) Acetonitrile:Methanol (1:1) with 1%Isopropylamine Isocratic Method 25% Co-solvent at80 mL/min SystemPressure 100 bar Column Temperature 25° C. Sample Diluent Methanol

Chiral Purity of Peaks was Determined by Following Analytical SFCMethod:

Column 4.6 × 100 mm CCS from ES Industries (West Berlin, NJ) CO₂Co-solvent Acetonitrile:Methanol (1:1) with 0.1% (Solvent B)Isopropylamine Isocratic Method 20% Co-solvent at 4 mL/min SystemPressure 100 bar Column Temperature 25° C. Sample Diluent MethanolPeak-1 (73a) 4.2 min  77 mg >95% ee 96.4% purity (UV 254) (UV 254)Peak-2 (73b) 4.9 min 100 mg >95% ee 96.4% purity (UV 254) (UV 254)

-   -   1. Peak-1 assigned as        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73a) (77 mg >95 ee) was repurified by flash column        chromatography (silica gel 4 g, eluting with CMA 80 in        chloroform 0 to 30%) to afford free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73a) (43 mg) as a white solid; Optical rotation: [α]_(D)=(+)        15.38 [CH₃OH, 1.3]; ¹H NMR (300 MHz, DMSO-d₆) δ 7.85-7.78 (m,        2H), 7.62-7.56 (m, 4H), 7.53 (d, J=4.7 Hz, 2H), 7.48-7.41 (m,        2H), 7.35 (d, J=2.3 Hz, 1H), 7.28 (dd, J=7.0, 1.6 Hz, 2H), 5.61        (s, 1H), 3.80 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.04 (q, J=4.6,        2.7 Hz, 1H), 0.54-0.38 (m, 2H), 0.24-0.09 (m, 2H); ¹⁹F NMR (282        MHz, DMSO-d₆) δ −60.75, −122.33. MS (ES+) 564.2 (M+1), 562.2        (M−1); To a solution of free base of        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73a) (26 mg) in methanol (4 mL) was added 2 N HCl (0.11 mL, 5        eq.), stirred for 15 mins and concentrated in vacuum to dryness        to afford        (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73a) (22 mg) hydrochloride salt as an off-white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.38 (s, 4H), 7.83 (d, J=1.8        Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.72 (t, J=1.8 Hz, 1H), 7.67        (s, 1H), 7.64-7.47 (m, 6H), 7.29 (d, J=1.2 Hz, 1H), 7.29-7.25        (m, 1H), 5.61 (s, 1H), 4.12 (s, 2H), 3.24 (d, J=6.8 Hz, 2H),        1.12-0.95 (m, 1H), 0.52-0.36 (m, 2H), 0.22-0.05 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.83, −121.91; MS (ES+) 564.3 (M+1),        (ES−) 562.2 (M−1); Analysis calculated for        C₃₀H₂₅F₄N₅O₂.HCl.0.75H₂O: C, 58.73; H, 4.52; N, 11.42; Found: C,        58.72; H, 4.72; N, 11.10.    -   2. Peak-2 assigned as        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73b) (100 mg, >95% ee) was repurified by flash column        chromatography (silica gel 12 g, eluting with 0-30% methanol in        chloroform) to furnish        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73b) (0.063 g) free base as a white solid; Optical rotation:        [α]_(D)=(−) 15.9 [CH₃OH, 1.3]; ¹H NMR: ¹H NMR (300 MHz, DMSO-d₆)        δ 7.88-7.76 (m, 2H), 7.65-7.49 (m, 5H), 7.47-7.38 (m, 2H), 7.30        (ddd, J=16.1, 5.9, 2.0 Hz, 3H), 5.61 (s, 1H), 3.77 (s, 2H), 3.24        (d, J=6.8 Hz, 2H), 1.05 (dddd, J=11.7, 8.2, 6.8, 2.7 Hz, 1H),        0.56-0.36 (m, 2H), 0.24-0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −60.74, −122.37; MS (ES⁺): MS (ES+) 564.3 (M+1), MS (ES−)        562.2 (M−1). HPLC: HPLC (Modified 5191 method, Zorbax SB-C3,        3.0×150 mm, 5 mm, with a ZGC SB-C3, 2.1×12.5 mm guard cartridge,        “A” Buffer=(98% of 0.1 M Ammonium Acetate in 2% acetonitrile)        “B” Buffer=100% Acetonitrile, UV Absorbance 250 nm; Rt=19.89 min        (99.33%)]. To a solution of free base of        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73b) (43 mg) in methanol (15 mL) was added 2 N HCl (0.19 mL, 5        eq.), stirred for 15 mins concentrated in vacuum to dryness to        afford        (−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (73b) (39 mg) hydrochloride salt as an off-white solid. ¹H NMR        (300 MHz, DMSO-d₆) δ 10.55 (s, 1H, D₂O exchangeable), 8.31 (s,        4H, D₂O exchangeable), 7.70-7.63 (m, 2H), 7.59-7.51 (m, 2H),        7.50-7.31 (m, 6H), 7.17-7.06 (m, 2H), 5.46 (s, 1H), 3.95 (q,        J=5.4 Hz, 2H), 3.08 (d, J=6.8 Hz, 2H), 0.89 (dddd, J=14.8, 6.7,        3.4, 2.0 Hz, 1H), 0.41-0.20 (m, 2H), 0.09-−0.08 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −60.82, −121.84; MS (ES+) 564.3 (M+1), MS        (ES−) 562.3 (M−1), 598.2 (M+Cl). Analysis calculated for:        C₃₀H₂₅F₄N₅O₂.H₂O.HCl: C, 58.30; H, 4.57; Cl, 5.74; N, 11.33;        Found: C, 58.46; H, 4.71; Cl, 5.93; N, 11.22.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(74a)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (0.2 g, 0.353 mmol) in 1,4-Dioxane (18 mL) was added hydrogenchloride (3.80 mL, 15.21 mmol) (4 M in 1,4-dioxane) and stirred at roomtemperature for 15 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. To the insolublecrude product added chloroform (40 mL), 2-cyclopropylethanol (1.520 g,16.94 mmol) and 2 g of silica gel. The mixture was concentrated invacuum to dryness and the slurry obtained was purified by flash columnchromatography [silica gel eluting with chloroform/CMA 80 (1:0 to 3:1)]to give1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(74a) (25 mg, 13%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.59-7.50 (m, 3H), 7.46-7.38 (m, 2H),7.36-7.20 (m, 7H), 7.14 (d, J=7.7 Hz, 1H), 5.42 (s, 1H), 3.77 (s, 2H),3.49-3.38 (m, 3H), 1.46 (q, J=6.7 Hz, 2H), 0.76 (ddt, J=10.3, 7.4, 3.7Hz, 1H), 0.41-0.32 (m, 2H), 0.05-0.00 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.72; MS (ES+): 535.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclobutylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(75a)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (0.2 g, 0.353 mmol) in 1,4-Dioxane (18 mL) was added hydrogenchloride (3.80 mL, 15.21 mmol) (4 M in 1,4-dioxane) and stirred at roomtemperature for 15 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. To the insolublecrude product added chloroform (40 mL), 2-cyclobutylmethanol (1.480 g,17.01 mmol), and 2 g of silica gel. The mixture was concentrated invacuum to dryness and the slurry obtained was purified by flash columnchromatography [silica gel eluting with chloroform/CMA 80 (1:0 to 3:1)]to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclobutylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(75a) (15 mg, 8%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 7.61 (s, 1H), 7.55 (d, J=9.4 Hz, 3H), 7.47-7.41 (m, 2H), 7.33(d, J=4.5 Hz, 5H), 7.24 (dd, J=8.8, 4.3 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H),5.39 (s, 1H), 3.80 (s, 2H), 3.37 (d, J=6.6 Hz, 2H), 2.05-1.89 (m, 3H),1.88-1.64 (m, 4H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.72; MS (ES+): 535.3(M+H).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76h) Step-1: Preparation of (5-Amino-3-fluorophenyl)methanol (76b)

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF(50 mL) was added dropwise at 0° C. a solution of5-amino-3-fluorobenzoic acid (76a) (5 g, 32.2 mmol) in THF (30 mL). Thereaction mixture was stirred at room temperature overnight. The mixturewas then cooled down to 0° C., quenched with ethyl acetate (30 mL) andwater (10 mL). The slurry obtained was filtered through celite andwashed with ethyl acetate (50 mL). The aqueous layer was separated andorganic layer was dried, filtered and concentrated in vacuum to drynessto give crude product. The crude was purified by flash columnchromatography (silica gel 80 g, eluting with 0-100% ethyl acetate inhexane) to furnish (5-amino-2-fluorophenyl)methanol (76b) (1.17 g, 8.29mmol, 25.7% yield) as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.76 (dd,J=10.1, 8.6 Hz, 1H), 6.65 (ddt, J=6.5, 2.9, 0.8 Hz, 1H), 6.39 (ddd,J=8.6, 4.3, 2.9 Hz, 1H), 5.10 (t, J=5.7 Hz, 1H), 4.91 (s, 2H), 4.41 (dt,J=5.8, 0.9 Hz, 2H); MS (ES+) 164.1 (M+23); (ES−) 140.0 (M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76c)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.992 g, 7.09 mmol), (5-amino-2-fluorophenyl)methanol (76b) (1 g, 7.09mmol), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop)(3.30 g, 7.09 mmol) was added N,N-dimethylformamide (43 mL) andN-ethyl-N-isopropylpropan-2-amine (6.17 mL) successively in a positiveflow of nitrogen at room temperature. The resulting reaction mixture wasstirred at room temperature for 37 h under nitrogen atmosphere. TLCanalysis (ethyl acetate/hexanes, v/v, 3/7) shows reaction was complete.The reaction was diluted with water (100 mL) and extracted with ethylacetate (2×100 mL), washed with brine (50 mL), the combined organiclayer was dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography (silicagel 40 g, eluting with ethyl acetate in hexanes from 0-100%) to furnish1-(3-Cyanophenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76c) (1.213 g, 42% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H, D₂O exchangeable), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt,J=7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.85-7.69 (m,3H), 7.56 (ddd, J=7.9, 4.6, 2.8 Hz, 1H), 7.13 (dd, J=9.8, 8.9 Hz, 1H),5.37 (t, J=5.6 Hz, 1H, D₂O exchangeable), 4.53 (d, J=5.6 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.96, −124.39; MS (ES⁺): MS (ES+) 405.1(M+1), 427.4 (M+Na), (ES−) 403.1 (M−1), 807.3 (2M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(4-fluoro-3-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76d)

To a stirred solution of1-(3-Cyanophenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76c) (1.205 g, 2.98 mmol) in dichloromethane (20 mL) was added sodiumbicarbonate (1.252 g, 14.90 mmol). Dess-Martin Periodinane (1.896 g,4.47 mmol) was added to the mixture and stirred at room temperature for5 h, TLC analysis (ethyl acetate/hexanes, 1:1, v/v) shows moderateconversion, at this time Dess-Martin Periodinane (1.896 g, 4.47 mmol)was added and stirred for 30 min. Excess solvent was pumped-off underreduced pressure, residue was diluted with water (50 mL), and extractedwith ethyl acetate (2×75 mL). The combined organic solvents wereevaporated to dryness. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish1-(3-cyanophenyl)-N-(4-fluoro-3-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76d) (0.552 g, 46.0% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.86 (d, J=37.4 Hz, 1H, D₂O exchangeable), 10.22 (d, J=4.9 Hz, 1H),8.39-8.30 (m, 1H), 8.24-7.82 (m, 5H), 7.80-7.69 (m, 1H), 7.45 (dd,J=10.3, 9.0 Hz, 1H); MS (ES⁺): MS (ES+) 403.11 (M+1), 425.15 (M+Na), MS(ES−) 401.1 (M−1), 803.1 (2M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76e)

To a solution of1-(3-cyanophenyl)-N-(4-fluoro-3-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76d) (0.528 g, 1.312 mmol) in THF (15 mL) cooled to 0° C. was addedphenyl magnesium bromide (2.66 mL, 2.66 mmol) The reaction mixture waswarmed to room temperature stirred for 3 h and quenched with saturatedaqueous NH₄Cl (100 mL). The product was extracted with ethyl acetate(100 mL, 75 mL). The combined organic extracts were washed with brine(50 mL), dried over anhydrous MgSO₄, filtered, evaporated to dryness.The residue obtained was purified by flash column chromatography[(silica gel 25 g, eluting with ethyl acetate in hexanes from 0 to100%)] to afford1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76e) (0.338 g, 54% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.72 (s, 1H, D₂O exchangeable), 8.17 (t, J=1.8 Hz, 1H), 8.01(dt, J=7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.83 (dd,J=6.6, 2.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.63 (m, 1H), 7.37-7.28 (m, 4H),7.23 (m, 1H), 7.11 (dd, J=9.9, 8.9 Hz, 1H), 6.11 (d, J=4.0 Hz, 1H, D₂Oexchangeable), 5.92 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.97, −123.11. MS (ES⁺): MS (ES+) 503.2 (M+Na), MS (ES−) 479.2 (M−1).

Step-5: Preparation of tert-butyl3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(76f)

To a stirred solution of1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76e) (0.333 g, 0.693 mmol) in anhydrous methanol (20 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (0.041 g, 0.173 mmol),(Boc)₂₀ (0.454 g, 2.07 mmol), followed by sodium borohydride (0.157 g,4.16 mmol) in small portions over 5 min. The reaction was exothermic andeffervescent. The reaction mixture was stirred for 1 h at 0° C., TLCanalysis (ethyl acetate/hexanes, 2/2, v/v) shows reaction was completeat this point N1-(2-aminoethyl)ethane-1,2-diamine (0.150 mL, 1.386 mmol)was added. The mixture was allowed to stir for 30 minutes andconcentrated in vacuum to dryness. The residue was treated with water(50 mL), and extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried over anhydrous MgSO₄, filtered and excesssolvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography (silica gel 25 g, eluting withethyl acetate/hexanes from 0 to 50%) to furnish tert-butyl3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(76f) (0.243 g, 60% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.76 (s, 1H), 7.81 (dd, J=6.6, 2.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H),7.49 (d, J=9.0 Hz, 1H), 7.46-7.39 (m, 2H), 7.38-7.28 (m, 6H), 7.23 (q,J=5.7, 4.5 Hz, 1H), 7.09 (t, J=9.4 Hz, 1H), 6.09 (d, J=4.0 Hz, 1H, D₂Oexchangeable), 5.92 (d, J=4.0 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 1.36 (s,9H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 10.77 (s, 1H), 7.81 (dd, J=6.5, 2.7Hz, 1H), 7.59 (s, 2H), 7.54-7.42 (m, 2H), 7.40 (s, 1H), 7.34 (dd,J=13.1, 3.1 Hz, 5H), 7.27-7.20 (m, 1H), 7.10 (t, J=9.4 Hz, 1H), 5.91 (s,1H), 4.19 (d, J=6.4 Hz, 2H), 1.36 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.81, −123.19; MS (ES⁺): MS (ES+) 607.2 (M+Na), MS (ES−) 583.3 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76g)

To a solution of tert-butyl3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(76f) (0.230 g, 0.393 mmol) in cyclopropylmethanol (3.39 mL, 47.2 mmol)was added ytterbium(III) trifluoromethanesulfonate (0.488 g, 0.787 mmol)and heated at 80° C. overnight. TLC analysis shows (CMA80/CHCl₃, 1/2,v/v) reaction was complete. Excess solvent was pumped-off, dried underreduced pressure. The residue was purified by flash columnchromatography (silica gel 12 g, eluting with CMA80 in chloroform from0-100%) to furnish1-(3-(aminomethyl)phenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76g) (139 mg, 73% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.75 (s, 1H, D₂O exchangeable), 7.83 (dd, J=6.6, 2.7 Hz, 1H), 7.64-7.55(m, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.48-7.40 (m, 2H), 7.32 (d, J=4.3 Hz,5H), 7.27-7.18 (m, 1H), 7.10 (dd, J=9.9, 8.9 Hz, 1H), 6.09 (d, J=4.0 Hz,1H, D₂O exchangeable), 5.91 (d, J=3.7 Hz, 1H), 3.77 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.74, −123.20; MS (ES⁺): MS (ES+) 485.2 (M+1), MS(ES−) 483.2 (M−1), 967.3 (2M−1).

Step-7: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76h)

To a solution of1-(3-(aminomethyl)phenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76g) (0.131 g, 0.27 mmol) in cyclopropylmethanol (2.330 mL, 32.4 mmol)was added Ytterbium(III) trifluoromethanesulfonate (0.503 g, 0.811 mmol)and heated at 80° C. overnight. TLC analysis shows (CMA80/CHCl₃, 1/2,v/v) reaction was completed. Excess solvent was pumped-off, dried underreduced pressure. The residue was purified by flash columnchromatography twice [silica gel 25 g, eluting with methanol inchloroform from 0-100%] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(76h) (78 mg, 54% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.80 (s, 1H), 7.76 (dd, J=6.5, 2.7 Hz, 1H), 7.64 (ddd,J=9.1, 4.7, 2.8 Hz, 1H), 7.59 (s, 1H), 7.56-7.51 (m, 1H), 7.43 (m, 2H),7.39-7.30 (m, 5H), 7.27 (m, 1H), 7.14 (t, J=9.4 Hz, 1H), 5.70 (s, 1H),3.78 (s, 2H), 3.27 (d, J=6.8 Hz, 2H), 1.05 (dddd, J=11.6, 8.1, 6.8, 2.6Hz, 1H), 0.58-0.37 (m, 2H), 0.22-0.08 (m, 2H); ¹H NMR (300 MHz, DMSO-d₆D₂O) δ 7.79 (dd, J=6.5, 2.7 Hz, 1H), 7.59 (ddd, J=9.1, 4.7, 2.8 Hz, 1H),7.55 (s, 1H), 7.54-7.50 (m, 1H), 7.49-7.44 (m, 2H), 7.41-7.27 (m, 6H),7.15 (dd, J=9.9, 8.9 Hz, 1H), 5.70 (s, 1H), 3.77 (s, 2H), 3.27 (d, J=6.8Hz, 2H), 1.09-0.99 (m, 1H), 0.55-0.39 (m, 2H), 0.23-0.07 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.74, −123.09; MS (ES⁺): MS (ES+) 539.2(M+1), MS (ES−) 537.2 (M−1), 573.2 (M+Cl); Analysis calculated for:C₂₉H₂₆F₄N₄O₂.0.5H₂O: C, 63.61; H, 4.97; N, 10.23; Found: C, 63.99; H,5.20; N, 9.89.

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77e) Step-1: Preparation of 4-fluoro-3-nitro-N-phenyl-N-propylaniline(77b)

To a 250 mL single-neck flask with a magnetic stir bar was charged4-bromo-1-fluoro-2-nitrobenzene (77a) (2.24 mL, 18.18 mmol),N-propylaniline (27a) (3.11 mL, 21.82 mmol), sodium2-methylpropan-2-olate (1.747 g, 18.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.052 g,1.818 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.499 g, 0.545mmol). The flask was degassed and refilled with nitrogen, this cycle wasrepeated three times. To the solid reactants, toluene (50 mL) wasinjected in a positive flow of nitrogen. The reaction mixture wasstirred at 110° C. for 16 h in a positive flow of nitrogen, cooled toroom temperature, quenched with water (75 mL) and extracted with ethylacetate (2×100 mL). The combined organic layers were dried over MgSO₄,filtered, evaporated to dryness. The residue was purified by flashcolumn chromatography twice [(silica gel 80 g, eluting with ethylacetate in hexanes from 0 to 100%)] to afford4-fluoro-3-nitro-N-phenyl-N-propylaniline (77b) (2.377 g, 8.67 mmol,47.7% yield) as a brown-yellow oil; MS (ES⁺): MS (ES+) 297.2 (M+Na).

Step-2: Preparation of 4-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine(77c)

To a solution of 4-fluoro-3-nitro-N-phenyl-N-propylaniline (77b) (2.35g, 8.57 mmol) in methanol (30 mL) was added palladium (10% Pd on carbon)(0.182 g, 1.714 mmol). The mixture was hydrogenated at 60 psi for 2.5 h.The reaction was filtered through a Celite pad, Celite pad wassubsequently washed with methanol (2×25 mL) and ethyl acetate (25 mL).Excess solvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography [(silica gel 80 g, eluting withethyl acetate in hexanes from 0 to 100%)] to afford4-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine (77c) (0.168 g, 8%yield) as a pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.16 (dd,J=8.7, 7.2 Hz, 2H), 6.93 (dd, J=11.4, 8.6 Hz, 1H), 6.79-6.71 (m, 3H),6.49 (dd, J=8.3, 2.7 Hz, 1H), 6.21 (ddd, J=8.6, 3.9, 2.7 Hz, 1H), 5.11(s, 2H, D₂O exchangeable), 3.61-3.44 (m, 2H), 1.67-1.44 (m, 2H), 0.88(t, J=7.4 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −140.87; MS (ES⁺): MS(ES+) 245.2 (M+1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77d)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.215 g, 0.766 mmol), 4-fluoro-N₁-phenyl-N₁-propylbenzene-1,3-diamine(77c) (0.156 g, 0.639 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 0.357 g, 0.766 mmol) was addedN,N-dimethylformamide (3.86 mL, 49.8 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) successively ina positive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under nitrogenatmosphere. Excess DMF was removed under reduced pressure. The reactionmixture was treated with water (25 mL) and was extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography [silicagel 25 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77d) (0.149 g, 46% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.51 (s, 1H, D₂O exchangeable), 8.11 (s, 1H), 7.99 (d, J=7.5Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.79-7.66 (m, 2H), 7.30-7.19 (m, 3H),7.18-7.12 (m, 2H), 6.96-6.85 (m, 3H), 3.59 (t, J=7.3 Hz, 2H), 1.54 (q,J=8.4, 7.9 Hz, 2H), 0.87 (td, J=7.4, 1.7 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.99, −129.31; IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CN stretching);MS (ES⁺): MS (ES+) 530.2 (M+Na), MS (ES−) 506.2 (M−1), 542.2 (M+Cl).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77e)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77d) (0.132 g, 0.260 mmol) in anhydrous methanol (10 mL) cooled to 0°C., were added nickel(II) chloride hexahydrate (0.062 g, 0.260 mmol)followed by sodium borohydride (0.059 g, 1.561 mmol) in small portionsover a period of 5 min. The reaction was exothermic and effervescent.The reaction mixture was stirred for 15 min, TLC analysis (ethylacetate/hexanes, 3/7, v/v) shows reaction was complete. Excess methanolwas pumped-off under reduced pressure. The reaction mixture was treatedwith water (30 mL), and product was extracted with ethyl acetate (2×50mL). The combined organic layers were dried over MgSO₄, filtered, andevaporated to dryness. The residue was purified by flash columnchromatography (silica gel 2×12 g, eluting with methanol/chloroform from0 to 100%) to furnish1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(77e) (0.039 g, 29% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.48 (s, 1H), 7.56 (s, 1H), 7.53-7.48 (m, 1H), 7.47-7.39 (m, 2H),7.37-7.28 (m, 1H), 7.28-7.10 (m, 4H), 6.96-6.82 (m, 4H), 3.77 (s, 2H),3.64-3.52 (m, 2H), 1.54 (h, J=7.4 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H); ¹HNMR (300 MHz, DMSO-d₆ D₂O) δ 7.55 (s, 1H), 7.53-7.48 (m, 1H), 7.47-7.38(m, 2H), 7.31 (dt, J=8.8, 2.4 Hz, 1H), 7.28-7.11 (m, 4H), 6.97-6.83 (m,4H), 3.76 (d, J=4.8 Hz, 2H), 3.58 (t, J=7.5 Hz, 2H), 1.54 (h, J=7.4 Hz,2H), 0.87 (t, J=7.3 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75,−129.58; MS (ES+): MS (ES+) 512.2 (M+1), MS (ES−) 510.2 (M−1); Analysiscalculated for C₂₇H₂₅F₄N₅O.0.75H₂O: C, 61.77; H, 5.09; N, 13.34; Found:C, 61.71; H, 5.03; N, 12.80.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78d) Step-1: Preparation of (E)- and(Z)-3-(3-cyclopropyl-1-phenylprop-1-enyl)aniline (78a)

To a stirred solution of1-(3-aminophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (46e) (0.17 g, 0.636mmol) in dichloromethane (15 mL) at 0° C. was added BF3.Et₂O (0.322 mL,2.54 mmol) and triethylsilane (0.203 mL, 1.272 mmol). The reactionwarmed to room temperature stirred for 30 minutes and quenched carefullywith saturated sodium bicarbonate solution. The reaction was stirred for5 mins and diluted with dichloromethane (50 mL). The organic layer wasseparated, washed with water (2×25 mL), brine (25 mL), dried, filteredand concentrated in vacuum. The crude residue was purified by flashcolumn chromatography (silica gel 12 g, eluting with ethyl acetate inhexanes 0 to 20%) to afford pure (E)- and(Z)-3-(3-cyclopropyl-1-phenylprop-1-enyl)aniline (78a) (151 mg, 95%yield) which was used as such for next step.

Step-2: Preparation of 3-(3-cyclopropyl-1-phenylpropyl)aniline (78b)

To a suspension of Pd on 10% carbon (32.0 mg) in ethyl acetate (25 mL)was added (E)- and (Z)-3-(3-cyclopropyl-1-phenylprop-1-enyl)aniline(78a) (150 mg, 0.602 mmol) and hydrogenated at 60 psi for 1 h. Thereaction mixture was filtered through celite and concentrated in vacuum.The crude residue was purified by flash column chromatography (silicagel 12 g, eluting with ethyl acetate in hexanes 0 to 30%) to afford3-(3-cyclopropyl-1-phenylpropyl)aniline (78b) (133 mg, 88% yield) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.25 (d, J=5.0 Hz, 4H), 7.19-7.09 (m,1H), 6.89 (t, J=7.7 Hz, 1H), 6.47 (t, J=1.9 Hz, 1H), 6.43 (dt, J=7.6,1.3 Hz, 1H), 6.33 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 4.95 (s, 2H), 3.73 (t,J=7.8 Hz, 1H), 2.02 (td, J=8.4, 6.6 Hz, 2H), 1.07 (qd, J=6.9, 1.9 Hz,2H), 0.77-0.59 (m, 1H), 0.42-0.30 (m, 2H), −0.03-0.11 (m, 2H).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(132 mg, 0.47 mmol) in DMF (5 mL) was added3-(3-cyclopropyl-1-phenylpropyl)aniline (78b) (130 mg, 0.517 mmol),N-ethyl-N-isopropylpropan-2-amine (0.655 mL, 3.76 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 241 mg,0.517 mmol) at room temperature. The resulting reaction mixture wasstirred at 25° C. for 16 h. The reaction mixture was quenched with water(25 mL) extracted and with ethyl acetate (2×50 mL). The organic layerswere combined, washed with water (25 mL), brine (25 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure todryness. The residue was purified by flash column chromatography (silicagel 12 g, eluting with hexanes in ethyl acetate/hexanes from 0-100%) tofurnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78c) (194 mg, 0.377 mmol, 80% yield) as an oil; MS (ES+) 537.3 (M+Na).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78d)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78c) (180 mg, 0.350 mmol) in anhydrous methanol (10 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (18.14 mg, 0.076 mmol),followed by sodium borohydride (83 mg, 2.188 mmol) in small portionsover 5 min. The reaction was exothermic and effervescent. The reactionmixture was stirred for 1 h at 0° C., TLC analysis (ethylacetate/hexanes, 2/2, v/v) shows reaction was complete at this pointN1-(2-aminoethyl)ethane-1,2-diamine (0.087 mL, 0.805 mmol) was added.The mixture was allowed to stir for 30 mins and concentrated in vacuumto dryness. The residue was treated with water (25 mL), and extractedwith ethyl acetate (2×25 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered and excess solvents were pumped-off underreduced pressure. The residue was purified by flash columnchromatography (silica gel 12 g, eluting with ethyl acetate/hexanes from0 to 50%) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78d) (165 mg, 0.318 mmol, 91% yield) free base as a white semisolid.The semisolid was dissolved in methanol (10 mL), added conc. HCl (0.043mL, 0.513 mmol), stirred for 15 mins and concentrated in vacuum todryness to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(78d) (100 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s,1H), 8.34 (s, 3H), 7.72 (s, 1H), 7.68-7.58 (m, 2H), 7.58-7.48 (m, 4H),7.34-6.59 (m, 5H), 7.16 (dp, J=8.6, 2.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H),4.13 (d, J=5.7 Hz, 2H), 3.92 (t, J=7.8 Hz, 1H), 2.08 (q, J=7.6 Hz, 2H),1.07 (dd, J=9.5, 6.3 Hz, 2H), 0.78-0.60 (m, 1H), 0.43-0.29 (m, 2H),−0.07 (td, J=5.4, 3.8 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.80; MS(ES+) 519.57 (M+1), (ES−) 517.2 (M−1); Analysis calculated forC₃₀H₂₉F₃N₄O.1.5HCl.1.25H₂O: C, 60.48; H, 5.58; Cl, 8.93; N, 9.40 Found:C, 60.12; H, 5.40; Cl, 8.65; N, 9.80.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79f) Step-1: Preparation of1-(3-Cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79a)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.463 g, 1.648 mmol) in DMF (10 mL) was added(3-aminophenyl)(pyridin-3-yl)methanol (31d) (0.33 g, 1.648 mmol)N-ethyl-N-isopropylpropan-2-amine (1.435 mL, 8.24 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 0.922 g,1.978 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 37 h under nitrogen atmosphere. The reaction wasdiluted with water (25 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layer was washed with brine (50 mL), dried,filtered, and evaporated to dryness. The residue obtained was purifiedby flash column chromatography [silica gel 40 g, eluting with ethylacetate in hexanes from 0-100%] to furnish1-(3-Cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79a) (0.653 g, 1.409 mmol, 86% yield) as a yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 10.67 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1.7Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90(ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.77-7.64 (m, 4H), 7.62-7.52 (m, 1H),7.37-7.25 (m, 2H), 7.21-7.14 (m, 1H), 6.15 (d, J=3.9 Hz, 1H), 5.77 (d,J=4.0 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES−) 462.2(M−1).

Step-2: Preparation of(Z)-1-(3-cyanophenyl)-N-(cyclopropylmethyl)-N′-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboximidamide(79b) and1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79c)

To a solution of1-(3-Cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79a) (0.32 g, 0.691 mmol) in dichloromethane (10 mL) at 0° C. was addedthionyl chloride (0.151 mL, 2.072 mmol), triethylamine (0.289 mL, 2.072mmol) and allowed to warm to room temperature over 3 h. The reactionmixture was concentrated in vacuum to dryness. The residue was dissolvedin acetonitrile (10.00 mL) and added cyclopropylmethanamine (1.198 mL,13.81 mmol). The reaction mixture was heated at reflux overnight. Thereaction mixture was cooled to room temperature concentrated in vacuumto dryness. The residue was diluted with chloroform (25 mL), washed withwater (10 mL), dried, filtered and concentrated in vacuum. The residuewas purified by flash column chromatography (silica gel 12 g, eluting0-100% ethyl acetate/methanol 9; 1 in hexane) to afford(Z)-1-(3-cyanophenyl)-N-(cyclopropylmethyl)-N′-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboximidamide(79b) (0.05 g, 0.088 mmol, 12.71% yield) as a colorless oil: ¹H NMR (300MHz, DMSO-d₆) δ 8.46 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.8, 1.7 Hz, 1H),7.89 (dt, J=7.8, 1.3 Hz, 1H), 7.84 (t, J=5.4 Hz, 1H), 7.60 (t, J=8.0 Hz,1H), 7.57-7.51 (m, 1H), 7.41-7.36 (m, 1H), 7.34 (t, J=1.8 Hz, 1H),7.30-7.22 (m, 2H), 6.80 (q, J=7.7 Hz, 2H), 6.19 (s, 1H), 5.91-5.84 (m,1H), 4.59 (s, 1H), 3.20 (s, 2H), 2.32-2.05 (m, 3H), 0.82 (d, J=17.1 Hz,1H), 0.56-0.47 (m, 2H), 0.42-0.33 (m, 2H), 0.27 (q, J=5.1 Hz, 2H),0.08-0.01 (m, 2H); MS ES(+) 570.3 (M+1), (ES−) 568.3 (ES−). Furtherelution gave1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79c) (0.07 g, 0.136 mmol, 19.63% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.62 (d, J=2.2 Hz, 1H), 8.44-8.37 (m,1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd,J=8.3, 2.2, 1.1 Hz, 1H), 7.82-7.66 (m, 5H), 7.57 (dt, J=7.9, 1.7 Hz,1H), 7.39-7.18 (m, 4H), 4.90 (s, 1H), 2.29 (t, J=6.2 Hz, 2H), 0.90 (t,J=12.0 Hz, 1H), 0.38 (td, J=5.7, 3.7 Hz, 2H), 0.13-0.02 (m, 2H); MS(ES+) 517.2 (M+1); (ES−) 515.2 (M−1).

Step-3: Preparation of tert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl)carbamate(79d) and tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(79e)

To a stirred solution of-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79c) (0.25 g, 0.484 mmol) in anhydrous methanol (5 mL), cooled to 0°C., was added di-tert-butyl dicarbonate (0.317 g, 1.452 mmol) andnickel(II) chloride hexahydrate (0.029 g, 0.121 mmol). Sodiumborohydride (0.110 g, 2.90 mmol) was added to the reaction mixture insmall portions over a 15 min period. The reaction mixture was stirredfor 15 min at 0° C. TLC (50% 9; 1 EtOAc/MeOH in hexanes) shows startingmaterial present. To the reaction mixture was added additionalnickel(II) chloride hexahydrate (0.029 g, 0.121 mmol) and sodiumborohydride (0.110 g, 2.90 mmol) in portions over 15 mins stirred for 30mins at 0° C. TLC shows no change can see two major product one has Rfsame as starting material. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.105 mL, 0.968 mmol) stirred for30 mins and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (25 mL) and water (25 mL). The organiclayer was separated and aqueous layer was extracted with dichloromethane(20 mL). The organic layers were combined washed with water (25 mL),brine (25 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel 24 g,eluting with 0-100% ethyl acetate in hexane to furnish tert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl)carbamate(79d) (0.036 g, 11.98% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.73 (s, 1H), 8.62 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.13 (d,J=7.9 Hz, 1H), 7.69-7.54 (m, 4H), 7.53-7.20 (m, 8H), 5.03 (s, 1H), 4.19(d, J=6.3 Hz, 2H), 2.40-0.90 (m, 2H), 0.93-0.84 (m, 1H), 0.45-0.32 (m,2H), 0.11-−0.00 (m, 3H)¹⁹F NMR (282 MHz, DMSO) δ −60.80; MS (ES+) 621.3(M+1). Further elution gave tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(79e) (0.030 g, 9.99% yield) as a white solid which has the same Rf asstarting material; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.61 (s,1H), 8.40 (d, J=4.9 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.59-7.19 (m, 11H),4.88 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.37-2.21 (m, 2H), 1.35 (s, 9H),1.00-0.79 (m, 1H), 0.43-0.33 (m, 2H), 0.09-0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO) δ −60.80; MS (ES+) 332.3 (½M+Na), 621.3 (M+1), (ES−) 619.3(M−1).

Step-4: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79f)

A solution of tert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl)carbamate(79d) (0.03 g, 0.048 mmol) and tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(79e) (0.030 g, 0.048 mmol) were dissolved separately in methanol (2.5mL) and added conc. HCL (0.073 mL, 2.42 mmol) and water (0.073 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. NMR of both the residue in methanol and TLC showssame compound. The products were combined dried and purified by flashcolumn chromatography (silica gel 4g, eluting with 0-150% methanol inchloroform to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(79f) (0.035 g, 66%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 11.00(s, 1H), 10.42 (s, 1H), 8.81 (s, 1H), 8.52 (s, 3H), 8.11 (s, 1H), 7.87(s, 1H), 7.73 (s, 2H), 7.68-7.59 (m, 2H), 7.58-7.48 (m, 2H), 7.42 (d,J=7.6 Hz, 3H), 5.59 (s, 1H), 4.11 (s, 2H), 2.81-2.56 (m, 2H), 1.21-1.01(m, 1H), 0.63-0.41 (m, 2H), 0.35-0.16 (m, 2H). ¹⁹F NMR (282 MHz, DMSO) δ−60.79; MS (ES+) 521.3 (M+1), (ES−) 555.2 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80h) Step-1: Preparation of 3-Amino-5-fluorobenzoic acid (80b)

To a solution of 3-fluoro-5-nitrobenzoic acid (80a) (2.5 g, 13.51 mmol)in methanol (30 mL) was added palladium (10% Pd on carbon) (0.287 g,2.70 mmol). The reaction mixture was hydrogenated at 60 psi for 2 h. TLCanalysis (ethyl acetate/hexanes, 1:1, v/v) shows reaction was complete.The reaction was filtered through a small Celite pad, Celite pad wassubsequently washed with methanol (2×25 mL) and ethyl acetate (25 mL).Excess solvents were pumped-off under reduced pressure afford3-Amino-5-fluorobenzoic acid (80b) (1.903 g, 91% yield) as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.93 (s, 1H, D₂O exchangeable),7.06-6.97 (m, 1H), 6.72 (ddd, J=9.4, 2.5, 1.4 Hz, 1H), 6.52 (dt, J=11.4,2.3 Hz, 1H), 5.71 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −113.44; MS (ES⁺): MS (ES+) 156.0 (M+1), MS (ES−) 153.9 (M−1).

Step-2: Preparation of (3-Amino-5-fluorophenyl)methanol (80c)

To a suspension of lithium aluminum hydride (1.209 g, 31.8 mmol), in THF(50 mL) was added drop-wise at 0° C. a solution of3-amino-5-fluorobenzoic acid (80b) (1.9 g, 12.25 mmol) in THF (30 mL)over a period of 30 min in a positive flow of nitrogen. The reactionmixture was stirred at room temperature for 14 h, cooled down to 0° C.,quenched carefully with ethyl acetate (50 mL) and stirred for 1 h. Thereaction was carefully quenched with water (50 mL) under a positive flowof nitrogen, filtered through a small Celite pad, and Celite pad waswashed with ethyl acetate (2×50 mL). The organic were evaporated todryness. The residue obtained was purified by flash columnchromatography [(silica gel 80 g, eluting with ethyl acetate/hexanesfrom 0 to 100%)] to furnish (3-Amino-5-fluorophenyl)methanol (80c)(0.594 g, 34% yield) as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ6.33 (dt, J=2.0, 1.1 Hz, 1H), 6.23-6.11 (m, 2H), 5.36 (s, 2H, D₂Oexchangeable), 5.12 (t, J=5.8 Hz, 1H), 4.33 (d, J=5.8 Hz, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −114.63; MS (ES⁺): MS (ES+) 142.02 (M+1), MS (ES−)140.00 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80d)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.375 g, 4.89 mmol), (3-amino-5-fluorophenyl)methanol (80c) (0.575 g,4.07 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 2.279 g, 4.89 mmol) wasN,N-dimethylformamide (24.60 mL, 318 mmol) andN-ethyl-N-isopropylpropan-2-amine (DIPEA) (3.55 mL, 20.37 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder nitrogen atmosphere. Excess DMF was pumped-off under reducedpressure. The reaction was diluted with water (75 mL) and extracted withethyl acetate (2×75 mL), the combined organic layer was dried overanhydrous MgSO₄, filtered, and evaporated to dryness. The residue waspurified by flash column chromatography [silica gel 25 g, eluting withethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80d) (1.416 g, 86% yield) as a white solid; ¹H NMR: (300 MHz, DMSO-d₆)δ 10.80 (s, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.02 (dt, J=7.7, 1.3 Hz, 1H),7.92 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.81-7.71 (m, 2H), 7.50-7.36 (m,2H), 6.90 (ddd, J=9.7, 2.4, 1.3 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H, D₂Oexchangeable), 4.49 (d, J=5.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.98, −112.56; MS (ES+): MS (ES+) 427.20 (M+Na), MS (ES−) 403.22(M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80e)

To a stirred solution of1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80d) (1.36 g, 3.36 mmol) in dichloromethane (20 mL) was added solidsodium bicarbonate (1.413 g, 16.82 mmol) followed byDess-MartinPeriodinane (2.140 g, 5.05 mmol) in one portion and stirredat room temperature for 6 h, TLC analysis (ethyl acetate/hexanes, 1:1,v/v) shows moderate conversion. To the reaction was added additionalDess-Martin Periodinane (2.140 g, 5.05 mmol) and stirred for 16 h.Excess solvent was pumped-off under reduced pressure. The reactionmixture was diluted with water (50 mL), and extracted with ethyl acetate(2×50 mL). The combined organic layer was dried over anhydrous MgSO₄;filtered, excess solvent was evaporated to dryness. The residue waspurified by flash column chromatography [(silica gel 25 g, eluting withethyl acetate/hexanes from 0 to 100%)] to furnish1-(3-cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80e) (0.910 g, 67% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.09 (s, 1H, D₂O exchangeable), 9.97 (d, J=1.5 Hz, 1H), 8.22 (t, J=1.8Hz, 1H), 8.06 (t, J=1.5 Hz, 1H), 8.03 (dt, J=7.8, 1.4 Hz, 1H), 7.95(ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84 (dt, J=10.8, 2.3 Hz, 1H), 7.80-7.74(m, 2H), 7.53 (ddd, J=8.4, 2.6, 1.3 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −60.99, −110.28; IR (KBr, cm⁻¹): 2236 cm⁻¹ (—CN stretching); MS (ES⁺):MS (ES+) 425.11 (M+Na), MS (ES−) 401.06 (M−1), 803.15 (2M−1).

Step-5: Preparation of1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80f)

A solution of1-(3-cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80e) (0.413 g, 1.027 mmol) in THF (20 mL) cooled to 0° C. was addedphenylmagnesium bromide (2.084 mL, 2.084 mmol). The reaction mixture wasallowed to warm to room temperature and stirred at room temperature for16 h. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) shows reaction wascomplete. The reaction was quenched with saturated aqueous NH₄Cl (30mL), and extracted with ethyl acetate (50 mL, 25 mL). The combinedorganic extracts were dried over anhydrous MgSO₄, filtered, andevaporated. The residue obtained was purified by flash columnchromatography [(silica gel 25 g, eluting with ethyl acetate in hexanesfrom 0 to 100%)] to afford1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80f) (155 mg, 31% yield) as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ10.81 (s, 1H, D₂O exchangeable), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt,J=7.8, 1.3 Hz, 1H), 7.95-7.85 (m, 1H), 7.82-7.65 (m, 2H), 7.53-7.41 (m,2H), 7.41-7.28 (m, 4H), 7.27-7.19 (m, 1H), 7.00 (dt, J=9.8, 1.7 Hz, 1H),6.10 (d, J=3.8 Hz, 1H, D₂O exchangeable), 5.69 (d, J=3.9 Hz, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −61.00, −112.17; IR (KBr, cm⁻¹): 2236 cm⁻¹ (—CNstretching); MS (ES⁺): MS (ES+) 503.1 (M+Na), MS (ES−) 479.1 (M−1),959.1 (2M−1).

Step-6: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80g)

To a solution of1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80f) (0.113 g, 0.235 mmol) in cyclopropylmethanol (1.689 mL, 23.52mmol) was added ytterbium(III) trifluoromethanesulfonate (0.292 g, 0.470mmol) and heated at 80° C. for 16 h. The reaction mixture was cooled toroom temperature, excess solvent was pumped-off under reduced pressure,and the residue was treated with water (30 mL), extracted withchloroform (2×30 mL), and filtered through Celite pad, excess solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography [silica gel 25 g, eluting with ethyl acetate inhexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80g) (31 mg, 25% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.86 (s, 1H, D₂O exchangeable), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt,J=7.8, 1.3 Hz, 1H), 7.95-7.87 (m, 1H), 7.79-7.69 (m, 2H), 7.56-7.47 (m,1H), 7.43 (s, 1H), 7.39-7.32 (m, 4H), 7.27 (dd, J=5.4, 2.9 Hz, 1H),7.05-6.94 (m, 1H), 5.48 (s, 1H), 3.29-3.21 (m, 2H), 1.13-1.00 (m, 1H),0.47 (dt, J=8.4, 2.5 Hz, 2H), 0.22-0.11 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.98, −111.79; MS (ES⁺): MS (ES+) 557.2 (M+Na), MS (ES−)533.2 (M−1), 569.0 (M+Cl).

Step-7: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80h)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80g) (0.026 g, 0.049 mmol) in anhydrous methanol (10 mL) cooled to 0°C., was added nickel(II) chloride hexahydrate (0.017 g, 0.073 mmol)followed by sodium borohydride (0.022 g, 0.584 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 minquenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.053 mL, 0.486mmol). Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL) andthe product was extracted with chloroform (2×30 mL). The combinedorganic layer was dried over anhydrous MgSO₄, filtered, evaporated todryness. The residue obtained was purified by flash columnchromatography [(silica gel 2×12 g, eluting with methanol/chloroformfrom 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(80h) (18 mg, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.91 (s, 1H, D₂O exchangeable), 7.60 (s, 1H), 7.50 (dt, J=11.5, 2.1 Hz,2H), 7.45-7.40 (m, 3H), 7.40-7.22 (m, 6H), 7.09-6.88 (m, 1H), 5.47 (s,1H), 3.77 (s, 2H), 3.24 (dd, J=6.8, 4.0 Hz, 2H), 1.15-0.98 (m, 1H),0.57-0.38 (m, 2H), 0.16 (tq, J=4.8, 2.9, 2.5 Hz, 2H); ¹H NMR (300 MHz,DMSO-d₆ D₂O) δ 7.58 (s, 1H), 7.50 (dd, J=4.1, 2.2 Hz, 2H), 7.48-7.40 (m,3H), 7.39-7.23 (m, 6H), 7.06-6.91 (m, 1H), 5.47 (s, 1H), 3.75 (s, 2H),3.24 (dd, J=6.8, 2.4 Hz, 2H), 1.15-0.99 (m, 1H), 0.47 (dt, J=9.2, 2.8Hz, 2H), 0.15 (td, J=5.6, 4.9, 3.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.76, −111.81; MS (ES⁺): MS (ES+) 539.2 (M+1), MS (ES−) 537.1 (M−1).

Preparation of(2S)-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl2-amino-3-methylbutanoate (81c) Step-1: Preparation of(2R)-(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl2-((tert-butoxycarbonyl)-amino)-3-methylbutanoate (81b)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (132 mg, 0.233 mmol) in DMF (4 mL) was added(S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (81a) (101 mg,0.466 mmol), N,N-dimethylpyridin-4-amine (29.0 mg, 0.235 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (90 mg, 0.468 mmol). The reaction mixture was stirred atroom temperature for 14 h, diluted with ethyl acetate (150 mL), washedwith water (2×75 mL), brine (75 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel 4 g, eluting with hexanes/ethyl acetate (1:0to 2:1)] to afford(2R)-(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl-2-((tert-butoxycarbonyl)-amino)-3-methylbutanoate(81b) (125 mg, 70%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.76 (d, J=4.2 Hz, 1H), 7.67-7.12 (m, 16H), 6.78 (s, 1H), 4.19 (d,J=6.2 Hz, 2H), 3.94 (ddd, J=8.1, 6.6, 3.7 Hz, 1H), 2.15-2.02 (m, 1H),1.36 (d, J=1.6 Hz, 18H), 0.80 (d, J=6.8 Hz, 6H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.82; MS (ES+): 766.5 (M+1).

Step-2: Preparation of(2S)-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl2-amino-3-methylbutanoate (81c)

A solution of(2R)-(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl-2-((tert-butoxycarbonyl)-amino)-3-methylbutanoate(81b) (60 mg, 0.078 mmol) in 1,4-Dioxane (4 mL) was treated withhydrogen chloride (0.830 mL, 3.32 mmol) (4 M in 1,4-dioxane) and stirredat room temperature for 14.5 h. The reaction mixture was treated withhexanes, decanted, washed with hexanes, and decanted again. Theinsoluble crude product was purified by flash column chromatography[silica gel, eluting with chloroform/CMA 80 (1:0 to 2:1)] to afford(2S)-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl2-amino-3-methylbutanoate (81c) (35 mg, 79% yield, as a mixture ofdiastereoisomers) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.89(d, J=3.7 Hz, 1H), 8.38 (s, 4H), 7.79 (d, J=2.0 Hz, 1H), 7.74-7.69 (m,2H), 7.67-7.49 (m, 4H), 7.47-7.32 (m, 6H), 7.29-7.23 (m, 1H), 6.92 (s,1H), 4.12 (s, 2H), 4.14-4.04 (m, 1H), 2.30-2.22 (m, 1H), 0.94-0.86 (m,6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −60.81; MS (ES+): 566.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82f) Step-1: Preparation of 3-nitrophenyl)(thiazol-2-yl)methanol (82b)

To a solution of 2-bromothiazole (82a) (1.8 mL, 17.42 mmol) in ether (12mL) at −78° C. was added dropwise n-BuLi (11.00 mL, 17.60 mmol) andstirred −78° C. for 2 h. To the 2-lithiated thiazole was added dropwisea solution of 3-nitrobenzaldehyde (31a) (2.63 g, 17.42 mmol) in THF (18mL) at −78° C. and stirred at −78° C. for 2 h and at room temperaturefor 2 h. The reaction mixture was quenched with saturated ammoniumchloride (50 mL). The organic layer was separated and aqueous layer wasextracted with ethyl acetate (75 mL). The organic layers were combinedwashed with brine (60 mL), dried, filtered and concentrated in vacuum todryness. The residue obtained was purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexane(1:0 to 2:1)] to give (3-nitrophenyl)(thiazol-2-yl)methanol (82b) (1.1g, 27%) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (ddd, J=2.2,1.4, 0.7 Hz, 1H), 8.16 (ddd, J=8.3, 2.4, 1.1 Hz, 1H), 7.93 (dddd, J=7.8,1.7, 1.1, 0.6 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H),7.67 (d, J=2.3 Hz, 1H), 7.20 (d, J=4.8 Hz, 1H), 6.17 (d, J=4.7 Hz, 1H);MS (ES+): 259.1 (M+23).

Step-2: Preparation of (3-aminophenyl)(thiazol-2-yl)methanol (82c)

To a solution of (3-nitrophenyl)(thiazol-2-yl)methanol (82b) (1.072 g,4.54 mmol) in methanol (27 mL) cooled to 0° C. was added nickel(II)chloride hexahydrate (0.270 g, 1.134 mmol) followed by sodiumborohydride (0.701 g, 18.15 mmol) portionwise over a period of 30 min.The reaction mixture was stirred at room temperature for 30 min,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.0 mL, 9.26 mmol),stirred for additional 30 min and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (75 mL), washed with water (60mL). The aqueous phase was extracted again with ethyl acetate (75 mL).The combined extracts were washed with brine (75 mL), dried over MgSO₄,filtered and concentrated in vacuum to dryness. The crude residue waspurified by flash column chromatography [silica gel 25 g, eluting withhexanes/ethyl acetate (1:0 to 0:1)] to afford(3-aminophenyl)(thiazol-2-yl)methanol (82c) (667 mg, 71%) as a yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (d, J=3.3 Hz, 1H), 7.60 (d,J=3.3 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.65-6.62 (m, 1H), 6.59-6.53 (m,2H), 6.43 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.74 (d, J=4.0 Hz, 1H), 5.07(s, 2H); MS (ES+): 207.1 (M+1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82d)

To a solution of (3-aminophenyl)(thiazol-2-yl)methanol (82c) (0.983 g,3.50 mmol) in N,N-dimethylformamide (26 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.872 g, 3.10 mmol), N-ethyl-N-isopropylpropan-2-amine (4.40 mL, 25.3mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(1.476 g, 3.1 mmol) at room temperature. The reaction mixture wasstirred at 25° C. for 16 h and diluted with ethyl acetate (200 mL). Thereaction mixture was washed with water (2×100 mL), brine (75 mL), driedover anhydrous MgSO₄, filtered and concentrated in vacuum to dryness.The residue obtained was purified by flash column chromatography [silicagel 12 g, eluting with hexanes/ethyl acetate (1:0 to 0:1) to afford1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82d) (1.113 g, 76%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 8.17 (t, J=1.7 Hz, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H),7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.58 (m, 6H), 7.31 (t, J=7.8Hz, 1H), 7.21 (dt, J=7.8, 1.4 Hz, 1H), 6.86 (d, J=4.2 Hz, 1H), 5.92 (d,J=4.2 Hz, 1H); MS (ES+): 470.1 (M+1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82e)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82d) (500 mg, 1.065 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.240 mL, 3.29 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was quenched with triethylamine (1.4 mL, 10.04 mmol) and stirred at room temperature for 1 h. Tothe chloro compound was added cyclopropylmethanol (8.00 mL, 97 mmol),triethyl amine (1.300 mL, 9.33 mmol) and concentrated in vacuum toremove most of dichloromethane. Triethyl amine (1.4 mL, 10.04 mmol) wasadded to reaction mixture and heated at 70° C. for 15 h and 120° C. for4 h. The reaction mixture was diluted with ethyl acetate and filtered.The filtrate was concentrated in vacuum and the residue was purified byflash column chromatography [silica gel eluting with hexanes/ethylacetate (1:0 to 2:1)] to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82e) (296 mg, 53%) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.53 (s, 1H), 7.98 (dd, J=2.1, 1.4 Hz, 1H), 7.84-7.78 (m, 1H), 7.72(ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.58-7.38 (m, 6H), 7.15 (t, J=7.9 Hz,1H), 6.99 (dt, J=7.6, 1.3 Hz, 1H), 5.60 (s, 1H), 0.95-0.81 (m, 1H),0.37-0.20 (m, 2H), 0.07-−0.08 (m, 2H); MS (ES+): 524.2 (M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82f)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82e) (233 mg, 0.445 mmol) in MeOH (10 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (23.00 mg, 0.097 mmol) followed bysodium borohydride (107 mg, 2.78 mmol) over a period of 5 min. thereaction mixture was stirred at room temperature for 1 h quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.912 mmol) stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (120 mL), washed with water (60mL). The aqueous phase was extracted again with ethyl acetate (60 mL).The organic extracts were combined washed with brine (60 mL), dried overMgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel 12 g, eluting withchloroform/CMA80 (1:0 to 3:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(82f) (54 mg, 23%) as a colorless gum. ¹H NMR (300 MHz, DMSO-d₆) δ 10.77(s, 1H), 7.73-7.68 (m, 3H), 7.65-7.59 (m, 1H), 7.59 (s, 1H), 7.54-7.51(m, 1H), 7.46-7.40 (m, 2H), 7.40-7.29 (m, 2H), 7.18 (dt, J=7.7, 1.3 Hz,1H), 5.78 (s, 1H), 3.77 (s, 2H), 3.37 (d, J=6.9 Hz, 2H), 1.10-1.04 (m,1H), 0.52-0.45 (m, 2H), 0.22-0.15 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ−60.73; MS (ES+): 528.2 (M+H).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83c) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoro-methyl)-1H-pyrazole-5-carboxamide(43d) (0.48 g, 1.036 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.240 mL, 3.29 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was quenched withtriethylamine (1.3 mL, 9.33 mmol) and stirred at room temperature for 1h. To the chloro compound was added cyclopropylmethanamine (1520 mg,20.74 mmol) and concentrated in vacuum to remove most ofdichloromethane. To the residue was added acetonitrile (15 mL) andheated at reflux for 16.5 h and concentrated in vacuum to dryness. Theresidue was treated with chloroform (150 mL), washed with water (75 mL),dried over MgSO₄ followed by filtration and concentration. The crudeproduct was purified by flash column chromatography [silica gel 12 g,eluting with chloroform/CMA80 (1:0 to 4:1)] to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83a) (119 mg, 22%) as a white semisolid; ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.47 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.16 (t, J=1.8 Hz,1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.94-7.87 (m, 1H), 7.79-7.15 (m, 9H),4.90 (s, 1H), 2.40-2.20 (m, 2H), 0.91 (s, 1H), 0.44-0.30 (m, 2H),0.09-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS (ES+): 517.3(M+1).

Step-2: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(83b)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83a) (72 mg, 0.139 mmol) in MeOH (4 mL) cooled with ice/water was addeddi-tert-butyl dicarbonate (92 mg, 0.418 mmol), nickel(II) chloridehexahydrate (7.0 mg, 0.029 mmol) followed by sodium borohydride (33.0mg, 0.856 mmol) over a period of 5 min. The reaction mixture was stirredat room temperature for 1 h followed by the addition of additionalnickel(II) chloride hexahydrate (5 mg) and sodium borohydride (23 mg)and stirring at room temperature for 0.5 h The reaction was quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.03 mL, 0.279 mmol) stirredat room temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (100 mL), washed with water (60mL). The aqueous phase was extracted again with ethyl acetate (60 mL).The organic extracts were combined washed with brine (60 mL), dried overMgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel 2×4 g, eluting withchloroform/CMA80 (1:0 to 4:1)] to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(83b) (13 mg, 15%); MS (ES+): 621.2 (M+H).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83c)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(83b) (13 mg, 0.021 mmol) in 1,4-Dioxane (3 mL) was added hydrogenchloride (0.23 mL, 0.922 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 17.5 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 3:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(83c) (5.3 mg, 49%) as a white semisolid. ¹H NMR (300 MHz, Methanol-d₄)δ 8.49 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.80-7.13 (m, 13H), 4.97 (s, 1H),3.86 (s, 2H), 2.46-2.28 (m, 2H), 1.02-0.81 (m, 1H), 0.54-0.39 (m, 2H),0.12-0.02 (m, 2H); ¹⁹F NMR (282 MHz, Methanol-d₄) δ −63.73; MS (ES+):521.2 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84h) Step-1: Preparation of(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(3-nitrophenyl)methanol (84b)

To a solution of 1-(1-ethoxyethyl)-4-iodo-1H-pyrazole (84a) (5 g, 18.79mmol) (Prepared as reported by Lin, Qiyan et al; Organic Letters 11(9):1999-2002 (2009)) in ether (16 mL) cooled to −78° C. was added dropwisea solution of n-butyllithium (12.0 mL, 19.2 mmol) in hexane followed bystirring for 30 mins at −78° C. To the anion formed was added a solutionof 3-nitrobenzaldehyde (31a) (2.87 g, 18.79 mmol) in THF (24 mL) slowlyat −78° C., stirred at −78° C. for 2 h and then at room temperature for2 h. The reaction mixture was quenched with saturated ammonium chloride(50 mL). The organic layer was separated and the aqueous phase wasextracted with ethyl acetate (75 mL). The organic layers were combinedwashed with brine (60 mL), dried over MgSO₄, filtered and concentratedin vacuum. The residue obtained was purified by flash columnchromatography [(silica gel 80 g, eluting with hexanes/ethyl acetate(1:0 to 1:1)] to furnish(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(3-nitrophenyl)methanol (84b) (3.537g, 64.6%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (s, 1H),8.11 (ddd, J=8.1, 2.4, 1.1 Hz, 1H), 7.82 (ddq, J=7.8, 1.8, 1.0 Hz, 1H),7.74 (d, J=0.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.37 (s, 1H), 6.04 (dd,J=4.8, 1.6 Hz, 1H), 5.85 (d, J=4.7 Hz, 1H), 5.47 (q, J=6.0 Hz, 1H),3.43-3.35 (m, 1H), 3.23-3.05 (m, 1H), 1.54 (d, J=6.0 Hz, 3H), 1.00 (td,J=7.0, 0.6 Hz, 3H); MS (ES+) 314.184 (M+Na).

Step-2: Preparation of(3-Aminophenyl)(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)methanol (84c)

To a solution of(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(3-nitrophenyl)methanol (84b) (3.437g, 11.80 mmol) in methanol (70 mL) cooled to 0° C. was added nickel(II)chloride hexahydrate (0.701 g, 2.95 mmol). Sodium borohydride (1.822 g,47.2 mmol) was added portionwise over a 30 mins period followed bystirring at room temperature for 30 min. The reaction mixture wasquenched with N1-(2-aminoethyl)ethane-1,2-diamine (2.60 mL, 24.07 mmol)and stirred at RT for 0.5 h. The reaction mixture was concentrated todryness and the residue was dissolved in ethyl acetate (240 mL) andwater (100 mL). The aqueous phase was separated and extracted with ethylacetate (100 mL). The organic layers were combined washed with brine(120 mL), dried over MgSO₄, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (Silica gel40 g, eluting with hexanes/ethyl acetate (1:0 to 0:1)] to afford(3-Aminophenyl)(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)methanol (84c) (3.104g, 100%) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.64-7.54 (m,1H), 7.27 (d, J=0.7 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.60 (t, J=1.9 Hz,1H), 6.50 (ddt, J=7.7, 1.7, 0.8 Hz, 1H), 6.45-6.32 (m, 1H), 5.53-5.39(m, 3H), 4.99 (s, 2H), 3.42-3.36 (m, 1H), 3.14 (dqd, J=9.6, 7.0, 1.3 Hz,1H), 1.59-1.41 (m, 3H), 1.01 (td, J=7.0, 0.8 Hz, 3H).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84d)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(3.19 g, 11.34 mmol) in DMF (90 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(84c) (3.19 g, 11.34 mmol), N-ethyl-N-isopropylpropan-2-amine (16.0 mL,92 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 5.40 g, 11.34 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was diluted with ethylacetate (300 mL), washed with water (2×120 mL), brine (120 mL), driedover MgSO₄, filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography [(silica gel 80 g, elutingwith hexanes/ethyl acetate (1:0 to 0:1)] to furnish1-(3-cyanophenyl)-N-(3-((1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84d) (4.766 g, 80%) as a light yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.65 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H),7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.62 (m, 4H), 7.60-7.50 (m,1H), 7.36-7.24 (m, 2H), 7.18-7.10 (m, 1H), 5.74 (dd, J=4.4, 1.9 Hz, 1H),5.64 (d, J=4.4 Hz, 1H), 5.46 (q, J=6.0 Hz, 1H), 3.44-3.35 (m, 1H),3.21-3.05 (m, 1H), 1.60-1.45 (m, 3H), 0.99 (td, J=7.0, 1.1 Hz, 3H).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84f)

To a solution of1-(3-cyanophenyl)-N-(3-((1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84d) (559 mg, 1.066 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.16 mL, 2.167 mmol) and allowed to warm to roomtemperature over a 2 h period. The reaction mixture was treated withtriethyl amine (0.91 mL, 6.53 mmol) and stirred at room temperature for1 h. The reaction mixture was quenched with cyclopropylmethanamine (1600mg, 21.82 mmol) and concentrated in vacuum to remove most ofdichloromethane. To the reaction mixture was added acetonitrile (15 mL),triethylamine (0.45 mL), heated at reflux for 17 h and concentrated invacuum to dryness. The residue obtained was dissolved in chloroform (150mL), washed with water (75 mL), dried over MgSO₄, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [silica gel 12 g, eluting withchloroform/methanol (1:0 to 9:1)] to furnish1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84f) (264 mg, 49%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.60(s, 1H), 10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz,1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78-7.69 (m, 2H), 7.67-7.50(m, 3H), 7.29 (dd, J=17.4, 9.7 Hz, 2H), 7.18 (d, J=7.6 Hz, 1H), 4.79 (s,1H), 2.37-2.09 (m, 3H), 0.86 (d, J=22.2 Hz, 1H), 0.37 (d, J=8.1 Hz, 2H),0.05 (t, J=5.9 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS (ES) 506(ES+).

Step-5: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(84g)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84f) (236 mg, 0.467 mmol) in MeOH (8 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (312 mg, 1.415 mmol) and nickel(II)chloride hexahydrate (60.0 mg, 0.253 mmol). Sodium borohydride (181 mg,4.69 mmol) was added slowly over 5 min and stirred at RT for 1 h. Thereaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine(0.230 mL, 2.110 mmol), stirred at RT for 0.5 h and concentrated invacuum to dryness. The residue obtained was dissolved in ethyl acetate(120 mL) and water (60 mL). The aqueous phase was separated andextracted with ethyl acetate (60 mL). The organic layers were combinedwashed with brine (60 mL), dried over MgSO₄, filtered and concentratedin vacuum. The residue obtained was purified by flash columnchromatography [silica gel 12 g, eluting with chloroform/methanol (1:0to 9:1)] to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(84g) (154 mg, 54%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.68 (s, 1H), 7.65-7.56 (m,2H), 7.56-7.38 (m, 5H), 7.38-7.31 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.16(d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.77 (s, 1H), 4.24-4.14 (m, 2H),2.33-2.19 (m, 2H), 1.37 (s, 9H), 0.95-0.80 (m, 1H), 0.44-0.28 (m, 2H),0.10-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81.

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84h)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(84g) (0.134 g, 0.22 mmol) in 1,4-Dioxane (15 mL) was added slowly asolution of 4 M hydrogen chloride in dioxane (2.4 mL, 9.60 mmol) andstirred at RT for 15 h. The reaction mixture was diluted with hexanesand decanted to remove solvent. The residue was treated with hexanes anddecanted again. The white residue was concentrated in vacuum to drynessand purified by flash column chromatography [silica gel 8 g, elutingwith chloroform/CMA80 (1:0 to 1:1)] to afford1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84h) (73 mg, 65%) free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 12.60 (bs, 1H), 10.68 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7.60-7.55 (m,2H), 7.54-7.33 (m, 6H), 7.26 (t, J=7.8 Hz, 1H), 7.20-7.14 (m, 1H), 4.77(s, 1H), 4.12 (s, 2H), 3.85 (s, 2H), 2.26 (dd, J=6.7, 3.9 Hz, 2H),0.96-0.82 (m, 1H), 0.42-0.32 (m, 2H), 0.07-0.01 (m, 2H); 19F NMR (282MHz, DMSO d₆) δ −60.74; MS (ES−) 507.9 (M−1). To a solution of free baseof1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84h) in methanol (5 mL) was added HCl (0.055 mL, 0.656 mmol) andconcentrated in vacuum to dryness. The residue obtained was dissolved inIPA (1 mL) by heating. To the clear solution was added ether (10 mL) andheated at reflux for 15 mins. The white solid obtained was collected byfiltration, washed with ether dried in vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(84h) (0.062 g, 0.100 mmol, 76% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.82 (s, 1H), 9.64 (s,1H), 8.44 (s, 3H), 7.91 (t, J=1.8 Hz, 1H), 7.84-7.70 (m, 4H), 7.66-7.49(m, 5H), 7.45 (t, J=7.9 Hz, 1H), 5.51 (t, J=6.3 Hz, 1H), 4.13 (q, J=5.8Hz, 2H), 2.75-2.58 (m, 2H), 1.14-1.00 (m, 1H), 0.59-0.48 (m, 2H), 0.30(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+) 510.3 (M+1); (ES−)508.3 (M−1); Analysis calculated for C₂₆H₂₆F₃N₇O.2.25HCl.2.25H₂O: C,49.40; H, 5.22; Cl, 12.62; N, 15.51; Found: C, 49.09; H, 5.18; Cl,12.99; N, 15.10.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(thiazol-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85c) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoro-methyl)-1H-pyrazole-5-carboxamide(82d) (500 mg, 1.065 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.240 mL, 3.25 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was treated with triethylamine (1.350 mL, 9.69 mmol) stirred at room temperature for 1 h, addedcyclopropylmethanamine (1600 mg, 21.82 mmol) and concentrated in vacuumto remove most of dichloromethane. To the reaction mixture was addedacetonitrile (15 mL) and triethylamine (0.7 mL). The reaction mixturewas refluxed for 15 h and concentrated in vacuum to dryness. The residuewas dissolved in chloroform (150 mL), washed with water (75 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The crudeproduct was purified by flash column chromatography [silica gel 2×12 g,eluting with hexanes/ethyl acetate (1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85a) (181 mg) as a brown solid. MS (ES+): 523.2 (M+1).

Step-2: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl-carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(85b)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85a) (170 mg, 0.325 mmol) in MeOH (6 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (217 mg, 0.986 mmol), nickel(II)chloride hexahydrate (42.0 mg, 0.177 mmol) followed by addition ofsodium borohydride (126 mg, 3.26 mmol) slowly over 5 min. The reactionmixture was stirred at room temperature, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.160 mL, 1.464 mmol), stirred for30 mins and concentrated in vacuum to dryness. The residue was treatedwith ethyl acetate (120 mL), washed with water (60 mL). The aqueousphase was extracted again with ethyl acetate (60 mL). The combinedorganic extracts were washed with brine (60 mL), dried over MgSO₄,filtered and concentrated in vacuum to dryness. The crude product waspurified by flash column chromatography [silica gel 2×4 g, eluting withchloroform/CMA80 (1:0 to 4:1)] to give tert-butyl3-(5-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl-carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(85b) (35 mg, 17%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.75(bs, 1H), 7.67 (s, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.63-7.18 (m, 10H), 5.15(d, J=3.1 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.45-2.28 (m, 2H), 1.36 (s,9H), 1.04-0.78 (m, 1H), 0.46-0.32 (m, 2H), 0.11-0.04 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.81; MS (ES+): 627.2 (M+1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85c)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(85b) (33 mg, 0.053 mmol) in 1,4-Dioxane (4 mL) was added hydrogenchloride (0.570 mL, 2.280 mmol) (4 M in 1,4-dioxane) and stirred at roomtemperature for 20.5 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel withchloroform/CMA80 (1:0 to 3:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85c) (24 mg, 87%) free base as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 10.73 (s, 1H), 7.69 (t, J=1.8 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.61(d, J=3.3 Hz, 1H), 7.60-7.51 (m, 3H), 7.47-7.41 (m, 2H), 7.35-7.31 (m,1H), 7.28 (d, J=7.9 Hz, 1H), 7.20 (dt, J=7.8, 1.4 Hz, 1H), 5.15 (s, 1H),3.79 (s, 2H), 2.88 (s, 2H), 2.38 (t, J=6.9 Hz, 2H), 1.02-0.83 (m, 1H),0.45-0.32 (m, 2H), 0.14-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.74; MS (ES+) 527.3 (M+1). To a solution of free base of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85c) (0.3 g, 0.570 mmol) in IPA (10 mL) was added conc. HCl (0.176 mL,2.117 mmol) and concentrated in vacuum to dryness. The residue was driedin vacuum to remove excess HCl and dissolved in IPA (5 mL) with heatingto solubilize. To the homogenous solution was added ether (50 mL) andheated at reflux for 30 mins. After cooling to room temperature thesolid obtained was collected by filtration, washed with ether and driedunder vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(85c) (0.27 g, 0.425 mmol, 74.5% yield) hydrochloride as a white solid.

¹H NMR (300 MHz, Deuterium Oxide) δ 7.61 (d, J=3.3 Hz, 1H), 7.46 (s,1H), 7.40 (d, J=3.3 Hz, 1H), 7.38-7.31 (m, 3H), 7.34-7.22 (m, 3H),7.21-7.12 (m, 2H), 5.76 (s, 1H), 3.97 (s, 2H), 2.80-2.60 (m, 2H),0.88-0.72 (m, 1H), 0.44-0.32 (m, 2H), 0.11-−0.08 (m, 2H); 19F NMR (282MHz, D₂O) 6-62.31; MS (ES+) 527.3 (M+1); (ES−) 525.2 (M−1); Analysiscalculated for C₂₆H₂₅F₃N₆OS.2.25HCl.2.5H₂O: C, 47.77; H, 4.97; Cl,12.20; N, 12.86; S, 4.91; Found: C, 48.01; H, 5.26; Cl, 11.94; N, 12.34;S, 4.85.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86g) Step-1: Preparation of (3-nitrophenyl)(pyridin-4-yl)methanol (86b)

A solution of 4-bromopyridine hydrochloride (4.8 g) in water (50 mL) wasneutralized with aq. 6 N NaOH followed by extraction with ethyl acetate(100 mL, 50 mL). The combined extracts were washed with brine (60 mL),dried over MgSO₄ followed by filtration and concentration to give4-bromopyridine (light brown oil, 1.65 g, low yield due to low boilingpoint, some loss from concentration). To a solution of 4-bromopyridine(1.58 g, 10.00 mmol) in Ether (8 mL) cooled to −78° C. was addeddropwise n-butyllithium (6.30 mL, 10.08 mmol) and stirred for 30 mins at−78° C. To the reaction mixture at −78° C. was added a solution of3-nitrobenzaldehyde (31a) (1.511 g, 10.00 mmol) in THF (12 mL), stirredat −78° C. for 2 h and then at room temperature for 2 h. The reactionmixture was quenched with saturated ammonium chloride (40 mL). Theorganic layer was separated and the aqueous phase was extracted withethyl acetate (60 mL). The combined organic extracts were washed withbrine (50 mL), dried over MgSO₄, filtered and concentrated in vacuum.The crude product was purified by flash column chromatography [silicagel 40 g, eluting with chloroform/methanol (1:0 to 19:1)] to afford(3-nitrophenyl)(pyridin-4-yl)methanol (86b) (1.005 g, 44%) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54-8.50 (m, 2H), 8.29 (t, J=2.0 Hz,1H), 8.12 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.86 (dt, J=7.8, 1.4 Hz, 1H),7.64 (t, J=7.9 Hz, 1H), 7.44 (ddd, J=4.6, 1.6, 0.7 Hz, 2H), 6.49 (d,J=4.2 Hz, 1H), 5.93 (d, J=4.1 Hz, 1H); MS (ES+): 231.1 (M+1).

Step-2: Preparation of (3-aminophenyl)(pyridin-4-yl)methanol (86c)

To a solution of (3-nitrophenyl)(pyridin-4-yl)methanol (86b) (953 mg,4.14 mmol) in methanol (25 mL) was cooled to 0° C. was added nickel(II)chloride hexahydrate (246 mg, 1.035 mmol) followed by sodium borohydride(639 mg, 16.56 mmol) portionwise over a 30 mins period. The reaction wasstirred at room temperature for 30 min, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.900 mL, 8.33 mmol), stirred for30 mins at room temperature and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (120 mL), washed with water (60mL). The aqueous phase was extracted again with ethyl acetate (75 mL).The combined organic extracts were washed with brine (75 mL), dried overMgSO₄, filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel 25 g, eluting withchloroform/methanol (1:0 to 9:1)] to give(3-aminophenyl)(pyridin-4-yl)methanol (86c) (655 mg, 79%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50-8.44 (m, 2H), 7.33 (ddd, J=4.4,1.6, 0.7 Hz, 2H), 6.93 (t, J=7.7 Hz, 1H), 6.60-6.48 (m, 2H), 6.40 (ddd,J=8.0, 2.3, 1.1 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H), 5.51 (d, J=3.9 Hz, 1H),5.04 (s, 2H).; MS (ES+): 201.1 (M+1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86d)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(892 mg, 3.17 mmol) in DMF (26 mL) was added(3-aminophenyl)(pyridin-4-yl)methanol (86c) (634 mg, 3.17 mmol),N-ethyl-N-isopropylpropan-2-amine (4.50 mL, 25.8 mmol) andbromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 1509mg, 3.17 mmol) and stirred at room temperature for 20 h. The reactionmixture was diluted with ethyl acetate (200 mL), washed with water(2×100 mL), brine (75 mL), dried over MgSO₄, filtered and concentratedin vacuum. The crude product was purified by flash column chromatography[silica gel 40 g, eluting with chloroform/methanol (1:0 to 9:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86d) (1.09 g, 74%) as a light yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.52-8.46 (m, 2H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.54 (m,4H), 7.35 (ddd, J=4.5, 1.6, 0.6 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.17(dt, J=7.8, 1.3 Hz, 1H), 6.21 (d, J=3.9 Hz, 1H), 5.70 (d, J=3.9 Hz, 1H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES+): 464.1 (M+1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86e)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86d) (0.4 g, 0.863 mmol) in dichloromethane (18 mL) at 0° C. was addedthionyl chloride (0.2 mL, 2.70 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was treated with triethylamine (1.1 mL, 7.89 mmol) stirred at room temperature for 1 h, addedcyclopropylmethanamine (1.3 g, 17.73 mmol) and concentrated in vacuum toremove most of dichloromethane. To the reaction mixture was addedacetonitrile (14 mL) and triethylamine (0.5 mL). The reaction mixturewas refluxed for 17.5 h and concentrated in vacuum to dryness. Theresidue was dissolved in chloroform (120 mL), washed with water (60 mL),dried over MgSO₄, filtered and concentrated in vacuum to dryness.

The crude product was purified by flash column chromatography [silicagel 2×12 g, eluting with chloroform/methanol (1:0 to 19:1) to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86e) (26 mg, 5.8%) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66(s, 1H), 8.49-8.44 (m, 2H), 8.18-8.15 (m, 1H), 8.01 (dt, J=7.8, 1.3 Hz,1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.62 (m, 3H), 7.56 (dt,J=8.1, 1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (t, J=7.8 Hz, 1H), 7.21 (dt,J=7.8, 1.4 Hz, 1H), 4.84 (s, 1H), 2.35-2.22 (m, 2H), 0.1.00-0.80 m, 1H),0.43-0.33 (m, 2H), 0.10-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.98; MS (ES+): 517.3 (M+1).

Step-5: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(86f)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86e) (24 mg, 0.046 mmol) in MeOH (3 mL) cooled with ice/water was addeddi-tert-butyl dicarbonate (31.0 mg, 0.141 mmol), nickel(II) chloridehexahydrate (6.0 mg, 0.025 mmol) followed by addition of sodiumborohydride (18 mg, 0.466 mmol) slowly over 5 min. The reaction mixturewas stirred at room temperature, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.022 mL, 0.203 mmol), stirred for30 mins and concentrated in vacuum to dryness. The residue was treatedwith ethyl acetate (120 mL), washed with water (60 mL). The aqueousphase was extracted again with ethyl acetate (60 mL). The combinedorganic extracts were washed with brine (60 mL), dried over MgSO₄,filtered and concentrated in vacuum to dryness. The crude product waspurified by flash column chromatography [silica gel 4 g, eluting withchloroform/CMA80 (1:0 to 4:1)] to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(86f) (12 mg, 42%) as a colorless gum. ¹H NMR (300 MHz, Methanol-d₄) δ8.47-8.40 (m, 2H), 7.65 (t, J=1.9 Hz, 1H), 7.52-7.19 (m, 10H), 4.92 (s,1H), 4.28 (s, 2H), 2.38 (dd, J=6.9, 3.0 Hz, 2H), 1.39 (s, 9H), 1.05-0.90(m, 1H), 0.51-0.42 (m, 2H), 0.08 (td, J=5.3, 4.8, 3.6 Hz, 2H); ¹⁹F NMR(282 MHz, Methanol-d₄) δ −63.71; MS (ES+): 621.2 (M+H).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86g)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(86f) (12 mg, 0.019 mmol) in 1,4-Dioxane (3 mL) was added hydrogenchloride (0.210 mL, 0.841 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 14 h. the reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel 2×4 g,eluting with chloroform/CMA80 (1:0 to 2:1) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(86g) (4.1 mg, 41%) as a colorless gum; ¹H NMR (300 MHz, Methanol-d₄) δ8.46-8.41 (m, 2H), 7.64 (t, J=1.9 Hz, 1H), 7.56 (s, 1H), 7.52-7.47 (m,4H), 7.46-7.40 (m, 2H), 7.35 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.22 (dt,J=7.7, 1.5 Hz, 1H), 4.92 (s, 1H), 3.93 (s, 2H), 2.38 (dd, J=6.9, 3.1 Hz,2H), 1.04-0.91 (m, 1H), 0.55-0.42 (m, 2H), 0.12-0.04 (m, 2H); ¹⁹F NMR(282 MHz, Methanol-d₄) δ −63.75; MS (ES+): 521.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87f) Step-1: Preparation of N-(2-cyclopropylethyl)aniline (87b)

To a 50 mL single-neck flask with a magnetic stir bar was charged sodium2-methylpropan-2-olate (0.673 g, 7.01 mmol),biphenyl-2-yldi-tert-butylphosphine (0.209 g, 0.701 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.321 g, 0.350 mmol) at thisstage flask was degassed and refilled with nitrogen, to this solidmixture 2-cyclopropylethanamine (87a) (0.662 mL, 7.01 mmol),bromobenzene (0.738 mL, 7.01 mmol), and toluene (10 mL) weresuccessively added in a positive flow of nitrogen. The reaction mixturewas stirred at room temperature for 16 h under a positive flow ofnitrogen. TLC analysis (ethyl acetate/hexanes, 5/95, v/v) shows reactionwas complete. Reaction mixture was filtered through a small Celite pad,Celite pad was subsequently washed with ethyl acetate (2×50 mL). Thecombined organics were dried over anhydrous MgSO₄, filtered, evaporatedto dryness. The residue was purified by flash column chromatography[(silica gel 40 g, eluting with ethyl acetate in hexanes from 0 to 20%)]to afford N-(2-cyclopropylethyl)aniline (87b) (198 mg, 18% yield) as anyellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 6.97 (dd, J=8.5, 7.2 Hz, 2H),6.59-6.31 (m, 3H), 5.44 (t, J=5.6 Hz, 1H, D₂O exchangeable), 2.97 (td,J=7.2, 5.6 Hz, 2H), 1.36 (q, J=7.0 Hz, 2H), 0.83-0.61 (m, 1H), 0.44-0.24(m, 2H), 0.06-−0.05 (m, 2H).

Step-2: Preparation of N-(2-cyclopropylethyl)-3-nitro-N-phenylaniline(87c)

To a 50 mL single-neck flask with a magnetic stir bar was charged1-bromo-3-nitrobenzene (27a) (0.245 g, 1.213 mmol) andN-(2-cyclopropylethyl)aniline (87b) (0.163 g, 1.011 mmol) was dissolvedin toluene (15 mL) and sodium 2-methylpropan-2-olate (0.078 g, 0.809mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.058g, 0.101 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.028 g,0.030 mmol) were added. The reaction mixture was stirred at 110° C. for16 h under a positive flow of nitrogen, cooled to room temperature, andexcess solvent was evaporated to dryness. Reaction was quenched withwater (25 mL), extracted with ethyl acetate (2×50 mL). The combinedorganics were dried over MgSO₄, filtered, evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 25 g,eluting with ethyl acetate in hexanes from 0 to 100%)] to as eluent toafford N-(2-cyclopropylethyl)-3-nitro-N-phenylaniline (87c) (280 mg, 98%yield) as a brown-yellow oil which was used as such in next step.

Step-3: Preparation ofN1-(2-cyclopropylethyl)-N₁-phenylbenzene-1,3-diamine (87d)

To a solution of N-(2-cyclopropylethyl)-3-nitro-N-phenylaniline (87c)(0.261 g, 0.924 mmol) in methanol (20 mL) was treated with palladium(10% Pd on carbon) (0.039 g, 0.370 mmol). The reaction mixture washydrogenated at 60 psi for 3 h at room temperature. TLC analysis (ethylacetate/hexanes, 1:1, v/v) shows reaction was complete. The reaction wasfiltered through a small Celite pad, Celite pad was subsequently washedwith methanol (2×25 mL), and ethyl acetate (25 mL). Excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography [(silica gel 25 g, eluting with ethyl acetate inhexanes from 0 to 100%)] to affordN1-(2-cyclopropylethyl)-N₁-phenylbenzene-1,3-diamine (87d) (0.066 g,0.262 mmol, 28.3% yield) as a brown waxy solid which was used as suchfor next step; MS (ES+) 253.2 (M+1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87e)

An oven-dried 100 mL round bottomed flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(105 mg, 0.374 mmol),N1-(2-cyclopropylethyl)-N1-phenylbenzene-1,3-diamine (87d) (63 mg, 0.250mmol), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP,0.140 g, 0.300 mmol) was added N,N-dimethylformamide (1.508 mL, 19.47mmol) and N-ethyl-N-isopropylpropan-2-amine (0.217 mL, 1.248 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder nitrogen atmosphere. Excess DMF was pumped-off under reducedpressure. The residue was purified by flash column chromatography[silica gel 25 g, eluting with ethyl acetate in hexanes from 0-100%] tofurnish1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87e) (93 mg, 72% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.4Hz, 1H), 7.94-7.86 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.67 (s, 1H),7.34-7.15 (m, 5H), 7.07-7.01 (m, 2H), 6.96 (t, J=7.3 Hz, 1H), 6.76-6.66(m, 1H), 3.75 (t, J=7.5 Hz, 2H), 1.45 (q, J=7.3 Hz, 2H), 0.68 (dd,J=12.8, 6.9 Hz, 1H), 0.44-0.33 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.95; MS (ES⁺): MS (ES+) 516.22 (M+1), 538.15 (M+Na),MS (ES−) 514.2 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87f)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87e) (81 mg, 0.157 mmol) in anhydrous methanol (10 mL) cooled to 0° C.was added nickel(II) chloride hexahydrate (0.056 g, 0.236 mmol) followedby sodium borohydride (0.071 g, 1.885 mmol) in small portions over aperiod of 5 min. The reaction was exothermic and effervescent. Thereaction mixture was stirred for 5 min, TLC analysis (ethylacetate/hexanes, 3/7, v/v) shows reaction was complete at this pointN1-(2-aminoethyl)ethane-1,2-diamine (0.170 mL, 1.571 mmol) was added.Excess methanol was pumped-off under reduced pressure. The reactionmixture was treated with saturated. aqueous NH₄Cl (50 mL), and productwas extracted with chloroform (2×50 mL). The combined organic layerswere combined dried over MgSO₄, filtered, evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 25 g,eluting with methanol in chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(87f) (32 mg, 39% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H), 7.56-7.49 (m, 2H), 7.46-7.40 (m, 2H), 7.34-7.16 (m, 6H),7.07-6.92 (m, 3H), 6.70 (dt, J=7.4, 2.0 Hz, 1H), 3.76 (d, J=7.9 Hz, 4H),1.45 (q, J=7.1 Hz, 2H), 0.70 (ddt, J=9.6, 7.5, 4.6 Hz, 1H), 0.47-0.31(m, 2H), 0.04 (dd, J=4.9, 1.5 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ7.50 (d, J=2.3 Hz, 2H), 7.48-7.41 (m, 2H), 7.37-7.22 (m, 4H), 7.19 (dd,J=4.8, 2.3 Hz, 2H), 7.10-6.93 (m, 3H), 6.70 (dt, J=6.7, 2.5 Hz, 1H),3.75 (d, J=3.3 Hz, 4H), 1.45 (q, J=7.2 Hz, 2H), 0.69 (tt, J=7.4, 4.8 Hz,1H), 0.45-0.35 (m, 2H), 0.08-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.71; MS (ES⁺): MS (ES+) 520.3 (M+1), MS (ES−) 518.3 (M−1); Analysiscalculated for: C₂₉H₂₈F₃N₅O.0.5H₂O: C, 65.90; H, 5.53; N, 13.25; Found:C, 66.12; H, 5.56; N, 12.85.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88a)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36b) (0.15 g, 0.312 mmol) in dichloromethane (10 mL) at 0° C. was addedthionyl chloride (0.046 mL, 0.624 mmol), and allowed to warm to roomtemperature and stirred for 3 h. The reaction mixture was concentratedin vacuum to dryness. The residue was dissolved in acetonitrile (10 mL)and added cyclopropylmethanamine (0.542 mL, 6.24 mmol). The reactionmixture was heated at reflux overnight. The reaction mixture was cooledto room temperature concentrated in vacuum to dryness. The residue waspurified by flash column chromatography (silica gel 25 g, eluting withethyl acetate in hexanes from 0-100%) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88b) (96 mg, 58% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.47 (s, 1H, D₂O exchangeable), 8.12 (s, 1H), 7.99 (dt,J=7.7, 1.3 Hz, 1H), 7.93-7.86 (m, 1H), 7.77-7.67 (m, 2H), 7.55 (t, J=7.1Hz, 1H), 7.48-7.34 (m, 3H), 7.29 (dd, J=8.4, 6.6 Hz, 2H), 7.24-7.14 (m,2H), 5.14 (s, 1H), 2.30 (t, J=6.3 Hz, 2H), 0.91 (s, 1H), 0.47-0.31 (m,2H), 0.05 (dd, J=5.7, 4.1 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.99,−127.84; MS (ES+): MS (ES+) 534.2 (M+1), MS (ES−) 532.14 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88a) (0.121 g, 0.227 mmol) in anhydrous methanol (10 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.081 g, 0.340 mmol)followed by sodium borohydride (0.103 g, 2.72 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 5 min, TLCanalysis (ethyl acetate/hexanes, 3/7, v/v) shows reaction was completeat this point N1-(2-aminoethyl)ethane-1,2-diamine (0.245 mL, 2.268 mmol)was added. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL), andproduct was extracted with chloroform (2×30 mL). The organic layers werecombined dried over MgSO₄, filtered, evaporated to dryness. The residuewas purified by flash column chromatography [(silica gel 25 g, elutingwith methanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(88b) (35 mg, 29% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.48 (s, 1H, D₂O exchangeable), 7.60-7.40 (m, 6H), 7.40-7.26 (m, 5H),7.19 (tdd, J=7.9, 4.7, 3.2 Hz, 2H), 5.14 (s, 1H), 3.78 (s, 2H), 2.30 (d,J=6.7 Hz, 2H), 1.03-0.78 (m, 1H), 0.45-0.33 (m, 2H), 0.04 (td, J=5.4,3.8 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −128.07; MS (ES⁺): MS(ES+) 538.3 (M+1), 560.2 (M+Na), MS (ES−) 536.2 (M−1), 572.2 (M+Cl);Analysis calculated for: C₂₉H₂₇F₄N₅O.0.25H₂O: C, 64.26; H, 5.11; N,12.92; Found: C, 64.26; H, 5.22; N, 12.58.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89g) Step-1: Preparation of 3-cyclopropyl-N-methoxy-N-methylpropanamide(89b)

To a solution of 3-cyclopropylpropanoic acid (89a) (1 g, 8.76 mmol) indichloromethane (10 mL) was added thionyl chloride (1.279 mL, 17.52mmol) at 0° C., one drop of DMF and stirred at room temperature for 3 h.To the reaction mixture was added N,O-dimethylhydroxylaminehydrochloride (1.282 g, 13.14 mmol), triethylamine (12.21 mL, 88 mmol)at room temperature and stirred for 16 h. The reaction mixture wasquenched with water (75 mL), and extracted with dichloromethane (75 mL,50 mL). The combined organics layers were dried MgSO₄, filtered, andevaporated to dryness. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-100%)] to furnish 3-cyclopropyl-N-methoxy-N-methylpropanamide(89b) (0.795 g, 5.06 mmol, 57.7% yield) as a light yellow oil; ¹H NMR(300 MHz, DMSO-d₆) δ 3.63 (s, 3H), 3.05 (s, 3H), 2.42 (t, J=7.5 Hz, 2H),0.76-0.61 (m, 1H), 0.38-0.30 (m, 2H), 0.04-−0.05 (m, 2H).

Step-2: Preparation of 1-(3-Aminophenyl)-3-cyclopropylpropan-1-one (89c)

To a stirred solution of 3-cyclopropyl-N-methoxy-N-methylpropanamide(89b) (0.75 g, 4.77 mmol) in tetrahydrofuran (10 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (47c) (7.16 mL,7.16 mmol) at 0° C. The reaction was stirred for 3 h at same temperatureand quenched by adding ammonium chloride solution (10 mL). The reactionwas extracted with ethyl acetate (2×25 mL). The organic layers werecombined washed with brine (25 mL), dried and concentrated in vacuum.The crude residue was purified by flash column chromatography (silicagel 40 g, eluting with 0-20% ethyl acetate in hexane) to furnish1-(3-aminophenyl)-3-cyclopropylpropan-1-one (89c) (0.758 g, 84% yield)as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.20-7.06 (m, 3H),6.84-6.74 (m, 1H), 5.33 (s, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.49 (q, J=7.2Hz, 2H), 0.74 (dddd, J=13.9, 10.0, 5.1, 2.2 Hz, 1H), 0.42-0.33 (m, 2H),0.10-0.01 (m, 2H); MS (ES+) 212.2 (M+Na); (ES−) 188.1 (M−1).

Step-3: Preparation of 1-(3-Aminophenyl)-3-cyclopropylpropan-1-ol (89d)

To a stirred solution of 1-(3-aminophenyl)-3-cyclopropylpropan-1-one(89c) (0.671 g, 3.55 mmol) in methanol (20 mL) was added sodiumborohydride (0.295 g, 7.80 mmol) at 0° C. and stirred the reaction for 1h at 0° C. TLC analysis (ethyl acetate/hexanes, 3/7, v/v) shows reactionwas complete. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was quenched with saturated aqueous sodium carbonatesolution (20 mL) and extracted with ethyl acetate (2×30 mL). The organiclayers were combined washed with brine (25 mL), dried over anhydrousMgSO₄, filtered, and evaporated to dryness. The residue was purified byflash column chromatography [(silica gel 25 g, eluting with ethylacetate in hexanes from 0 to 50%)] to furnish1-(3-Aminophenyl)-3-cyclopropylpropan-1-ol (89d) (431 mg, 67% yield) asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.92 (t, J=7.7 Hz, 1H), 6.53(t, J=1.8 Hz, 1H), 6.47-6.34 (m, 2H), 4.95 (s, 2H, D₂O exchangeable),4.90 (d, J=4.2 Hz, 1H, D₂O exchangeable), 4.35 (m, 1H), 1.74-1.51 (m,2H), 1.31-1.04 (m, 2H), 0.59-0.69 (m, 1H), 0.43-0.29 (m, 2H), −0.05 (dq,J=3.6, 2.4, 1.8 Hz, 2H); MS (ES⁺): MS (ES+) 192.1 (M+1), MS (ES−) 190.1(M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.922 g, 3.28 mmol), 1-(3-aminophenyl)-3-cyclopropylpropan-1-ol (89d)(0.418 g, 2.185 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (1.223 g, 2.62 mmol) were treatedwith N,N-dimethylformamide (DMF) (14 mL) andN-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.903 mL, 10.93 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder a positive flow of nitrogen atmosphere. Excess DMF was pumped-offunder reduced pressure. The residue was treated with water (30 mL), andextracted with ethyl acetate (2×30 mL) combined organics were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue was thenpurified by flash column chromatography [silica gel 25 g, eluting withethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (918 mg, 92% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.63 (s, 1H, D₂O exchangeable), 8.17 (t, J=1.9 Hz, 1H), 8.01 (dt,J=7.8, 1.3 Hz, 1H), 7.92 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.81-7.69 (m,2H), 7.61 (t, J=1.9 Hz, 1H), 7.53 (dt, J=8.2, 1.4 Hz, 1H), 7.27 (t,J=7.8 Hz, 1H), 7.07 (dt, J=7.8, 1.3 Hz, 1H), 5.18 (d, J=4.6 Hz, 1H, D₂Oexchangeable), 4.50 (d, J=7.8 Hz, 1H), 1.64 (ddd, J=8.9, 6.4, 3.2 Hz,2H), 1.18 (td, J=7.0, 2.1 Hz, 2H), 0.73-0.57 (m, 1H), 0.42-0.27 (m, 2H),−0.02-−0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.96; IR (KBr,cm⁻¹): 2236 cm⁻¹ (—CN stretching); MS (ES+): MS (ES+) 455.2 (M+1),477.19 (M+Na), MS (ES−) 453.02 (M−1), 488.8 (M+Cl).

Step-5: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89f)

To a solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (0.406 g, 0.893 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.196 mL, 2.68 mmol), allowed to warm to roomtemperature and stirred for 3 h. The reaction mixture was treated with1H-imidazole (0.608 g, 8.93 mmol) followed by stirring at roomtemperature for 5 h. The reaction mixture was evaporated to dryness. Theresidue obtained was dissolved in N,N dimethyl acetamide (20 mL) added1H-imidazole (0.608 g, 8.93 mmol) and heated to 130° C. for 36 h. TLCanalysis shows reaction was complete. Excess solvent was pumped-offunder reduced pressure. The residue was diluted with water (30 mL) andextracted with ethyl acetate (2×30 mL). The organic layers were combineddried over anhydrous MgSO₄, filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [silica gel 25 g,eluting with ethyl acetate in hexanes from 0-100% then methanol inchloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89f) (44 mg, 10% yield) as a waxy solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H, D₂O exchangeable), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt,J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.84-7.68 (m,3H), 7.63-7.55 (m, 2H), 7.40-7.30 (m, 1H), 7.27 (t, J=1.2 Hz, 1H), 7.15(dt, J=7.7, 1.4 Hz, 1H), 6.90 (t, J=1.1 Hz, 1H), 5.35 (dd, J=9.2, 6.5Hz, 1H), 2.38-2.11 (m, 2H), 1.07 (ddq, J=29.2, 15.0, 7.6, 7.1 Hz, 2H),0.71 (p, J=6.0 Hz, 1H), 0.44-0.33 (m, 2H), −0.04 (ddd, J=6.5, 4.6, 3.3Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.96; MS (ES⁺): MS (ES+) 505.2(M+1), MS (ES−) 503.2 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89f) (0.039 g, 0.077 mmol) in anhydrous methanol (10 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.028 g, 0.116 mmol)followed by sodium borohydride (0.035 g, 0.928 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 5 min, TLCanalysis (methanol/chloroform, 2/8, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (0.084 mL, 0.773 mmol)was added. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL), andproduct was extracted with chloroform (2×30 mL). the organic layers werecombined dried over MgSO₄, filtered, evaporated to dryness. The residuewas purified by flash column chromatography [(silica gel 2×12 g, elutingwith methanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89g) (15 mg, 38% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.76 (s, 1H, D₂O exchangeable), 7.80 (t, J=1.1 Hz, 1H), 7.62-7.51 (m,4H), 7.48-7.41 (m, 2H), 7.37-7.29 (m, 2H), 7.27 (t, J=1.3 Hz, 1H), 7.13(dt, J=7.7, 1.3 Hz, 1H), 6.89 (t, J=1.1 Hz, 1H), 5.34 (dd, J=9.2, 6.4Hz, 1H), 3.80 (s, 2H), 2.38-2.08 (m, 2H), 1.19-0.89 (m, 2H), 0.70 (ddt,J=10.4, 7.3, 4.0 Hz, 1H), 0.45-0.29 (m, 2H), −0.04 (td, J=5.2, 3.7 Hz,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73; MS (ES⁺): MS (ES+) 509.2(M+1), MS (ES−) 507.22 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90f) Step-1: Preparation of (2-Amino-3-fluorophenyl)methanol (90b)

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF(20 mL) was added dropwise at 0° C. a solution of methyl2-amino-3-fluorobenzoate (90a) (5 g, 32.2 mmol) in THF (20 mL). Thereaction mixture was stirred at room temperature overnight. The mixturewas then cooled down to 0° C., quenched with ethyl acetate (30 mL) andwater (10 mL). The slurry obtained was filtered through celite andwashed with ethyl acetate (50 mL). The aqueous layer was separated andorganic layer was dried, filtered and concentrated in vacuum to drynessto give crude product. The crude was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (2-Amino-3-fluorophenyl)methanol (90b) (2.958 g, 65%yield) as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.98-6.86 (m, 2H),6.52 (td, J=7.8, 5.2 Hz, 1H), 5.15 (t, J=5.5 Hz, 1H), 4.88 (s, 2H), 4.43(d, J=5.5 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −136.17 (dd, J=11.3, 5.2Hz); MS (ES+) 165 (M+Na); (ES−) 140.0 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(4 g, 14.23 mmol) in DMF (86 mL) was added(2-amino-3-fluorophenyl)methanol (90b) (2.008 g, 14.23 mmol),N-ethyl-N-isopropylpropan-2-amine (DIPEA, 12.39 mL, 71.1 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 6.63 g,14.23 mmol) at room temperature. The resulting reaction mixture wasstirred at room temperature for 37 h under nitrogen atmosphere. Thereaction was diluted with water (100 mL) and extracted with ethylacetate (2×100 mL). The organic layers were combined washed with brine(50 mL), dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography [silicagel 80 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90c) (0.709 g, 12% yield) as a white solid; MS (ES−) 403.2 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90d)

To a stirred suspension of1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90c) (0.879 g, 2.174 mmol) in dichloromethane (20 mL) containing sodiumbicarbonate (0.913 g, 10.87 mmol) was added Dess-MartinPeriodinane(1.383 g, 3.26 mmol) and stirred at room temperature for 3h, TLCanalysis (ethyl acetate/hexanes, 1:1, v/v) shows good conversion. Thereaction mixture was filtered through a Celite pad, and Celite pad waswashed with ethyl acetate, filtrate was concentrated in vacuum todryness. The residue was purified by flash column chromatography[(silica gel 25 g, eluting with ethyl acetate in hexanes from 0 to100%)] to afford1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90d) (154 mg, 18% yield) as a white solid; MS (ES+) 425.08 (M+1), MS(ES−) 401.1 (M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90e)

A solution of1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90d) (0.148 g, 0.368 mmol) in THF (4 mL) cooled to 0° C. was addedphenylmagnesium bromide (0.747 mL, 0.747 mmol) and stirred at roomtemperature for 14 h. Reaction was quenched with saturated aqueous NH₄Cl(25 mL), extracted with ethyl acetate (2×25 mL). The combined extractswere dried over MgSO₄, filtered, evaporated under reduced pressure. Theresidue was purified by flash column chromatography [(silica gel 25 g,eluting with ethyl acetate in hexanes from 0 to 50%)] to furnish1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90e) (92 mg, 52% yield) as a pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 10.30 (s, 1H, D₂O exchangeable), 7.97 (dt, J=6.9, 1.7 Hz, 1H), 7.90(d, J=1.9 Hz, 1H), 7.74-7.66 (m, 2H), 7.62 (s, 1H), 7.46-7.34 (m, 2H),7.28-7.18 (m, 6H), 6.04 (s, 1H, D₂O exchangeable), 5.97 (s, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.9, −119.75; MS (ES⁺): MS (ES+) 503.1 (M+Na), MS(ES−) 479.1 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90f)

To a stirred solution of1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90e) (0.051 g, 0.106 mmol) in anhydrous methanol (10 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.038 g, 0.159 mmol)followed by sodium borohydride (0.048 g, 1.274 mmol) in small portionsover a period of 5 min. TLC analysis (methanol/chloroform, 2/8, v/v)shows reaction was complete at this pointN1-(2-aminoethyl)ethane-1,2-diamine (0.115 mL, 1.062 mmol) was added.Excess methanol was pumped-off under reduced pressure. The reactionmixture was treated with saturated aqueous NH₄Cl (30 mL), and productwas extracted with chloroform (2×30 mL), combined organic layer wasdried over MgSO₄, filtered, evaporated to dryness. The residue waspurified by flash column chromatography [(silica gel 25 g, eluting withmethanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90f) (43 mg, 84% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.47-7.40 (m, 3H), 7.40-7.33 (m, 3H), 7.31-7.13 (m, 7H), 5.96 (s, 1H),3.75 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.74, −119.59; MS (ES⁺): MS(ES+) 485.1 (M+1), 969.2 (2M+1), MS (ES−) 483.1 (M−1), 967.2 (2M−1);Analysis calculated for: C₂₅H₂₀F₄N₄O₂: C, 61.98; H, 4.16; N, 11.57;Found: C, 61.91; H, 4.43; N, 11.61.

Preparation of(E/Z)-1-(3-(Aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylprop-1-enyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (91a)

To a stirred solution of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(46g) (0.33 g, 0.617 mmol) in acetone (10 mL) was added conc. HCl (0.154mL, 1.852 mmol) and stirred with heating for 15 mins. The reactionmixture was concentrated in vacuum to dryness. The residue obtained wasdissolved in IPA (2.0 mL) and heated to reflux, ether (40 mL) was addedto the hot solution and continued heating at reflux for 15 mins. Thereaction mixture was cooled to room temperature and solid obtained wascollected by filtration, dried in vacuum to furnish(E/Z)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylprop-1-enyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (91a) (0.251 g, 0.454 mmol, 73.5% yield) as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (d, J=13.2 Hz, 1H), 8.38 (s, 3H),7.74-7.68 (m, 2H), 7.67-7.47 (m, 4H), 7.46-7.22 (m, 5H), 7.15 (ddt,J=16.5, 6.0, 1.6 Hz, 2H), 6.93 (ddt, J=7.6, 2.8, 1.3 Hz, 1H), 6.17 (dt,J=12.0, 7.4 Hz, 1H), 4.12 (s, 2H), 2.00-1.89 (m, 2H), 0.86-0.70 (m, 1H),0.48-0.36 (m, 2H), 0.06 (td, J=5.0, 1.4 Hz, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −60.81, −60.82; MS (ES−) 515.3 (M−1); Analysis calculated forC₃₀H₂₇F₃N₄O.HCl: C, 65.16; H, 5.10; Cl, 6.41; N, 10.13; Found: C, 64.75;H, 5.30; Cl, 6.21; N, 9.85.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92g) Step-1: Preparation of(E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (92b)

To a stirred solution of 1-(pyridin-4-yl)ethanone (92a) (1.516 mL, 13.27mmol) in methanol (100 mL) cooled to 0° C. was addedcyclopropanecarboxaldehyde (1.5 mL, 19.90 mmol) and aqueous potassiumhydroxide (1N, 2.65 mL, 2.65 mmol). The reaction was allowed to warm toroom temperature overnight. The reaction was acidified with 1Nhydrochloric acid and concentrated in vacuum to remove methanol. Thecrude residue was dissolved in ethyl acetate (100 mL) washed with sodiumcarbonate solution, water (2×50 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography (silica gel, 12 g, eluting with ethyl acetate in hexanes0 to 100%) to afford pure(E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (92b) (479 mg,20.85%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.89-8.59 (m, 2H), 7.91-7.71 (m,2H), 7.19 (d, J=15.1 Hz, 1H), 6.58 (dd, J=15.1, 10.4 Hz, 1H), 1.88-1.71(m, 1H), 1.10-0.96 (m, 2H), 0.87-0.72 (m, 2H).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (92c)

To Pd/C (138 mg, 0.130 mmol) in methanol (50 mL) was added(E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (92b) (450 mg, 2.60mmol) and hydrogenated at 60 psi for 1 h. The reaction mixture wasfiltered through celite and filtrate concentrated in vacuum. The cruderesidue was purified by flash column chromatography (silica gel, 12 g,eluting with ethyl acetate in hexane 0-100%) to afford3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92c) (323 mg, 70.1%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.58-8.37 (m, 2H), 7.31 (ddd, J=4.5,1.6, 0.6 Hz, 2H), 5.36 (d, J=4.7 Hz, 1H), 4.67-4.41 (m, 1H), 1.66 (tdd,J=7.7, 5.7, 3.0 Hz, 2H), 1.28-1.16 (m, 2H), 0.73-0.56 (m, 1H), 0.43-0.25(m, 2H), 0.06-−0.12 (m, 2H).

Step-3: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (92d)

To a stirred solution of 3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92c)(0.3 g, 1.693 mmol) in dichloromethane (10 mL) at 0° C. was added NaHCO₃(0.427 g, 5.08 mmol) and Dess-MartinPeriodinane (1.436 g, 3.39 mmol).The reaction mixture was stirred at 0° C. for 30 minutes and warmed toroom temperature in 15 mins. The reaction was stirred at roomtemperature for 1 hr and quenched by adding aqueous saturated sodiumbicarbonate (25 mL), extracted with dichloromethane (2×50 mL). Theorganic layers were combined, washed with water (2×25 mL), brine (25mL), dried, filtered and concentrated in vacuum. The crude residue waspurified by column chromatography (silicagel, 12 g, eluting with 0-30%ethyl acetate in hexane) to afford3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (92d) (290 mg, 98%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 3.14 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1Hz, 2H), 0.75 (dddd, J=12.0, 8.1, 7.0, 2.8 Hz, 1H), 0.47-0.28 (m, 2H),0.14-0.02 (m, 2H).

Step-4: Preparation of1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92e)

To a stirred solution of 3-cyclopropyl-1-(pyridin-4-yl)propan-1-one(92d) (250 mg, 1.427 mmol) in tetrahydrofuran (20 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (2.2853 mL,2.2853 mmol) at 0° C. Reaction was allowed to warm to room temperatureand stirred for 2 h. The reaction was quenched with ammonium chloridesolution (25 mL), extracted with ethyl acetate (2×50 mL). the organiclayers were combined, washed with water (2×25 mL), brine (25 mL), dried,filtered and concentrated in vacuum. The crude residue was purified byflash column chromatography (silicagel, 25 g eluting with CMA 80 inchloroform 0-100%) to afford1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92e) (430mg, 1.602 mmol, 112% yield). This was pure enough to be used as such innext step; MS (ES+) 269.2 (M+1).

Step-5: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92f)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(178 mg, 0.633 mmol) in DMF (5 mL) was added1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92e) (204mg, 0.760 mmol), N-ethyl-N-isopropylpropan-2-amine (0.883 mL, 5.07 mmol)and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 325mg, 0.697 mmol) at room temperature and stirred at 25° C. for 16 h. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (100 mL, 50 mL). The organic layers were combined and dried overanhydrous MgSO₄, filtered, concentrated under reduced pressure todryness. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with CMA 80 in chloroform0-100%) to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92f) (320 mg, 95% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 10.63(s, 1H), 8.48-8.42 (m, 2H), 8.16 (d, J=2.2 Hz, 1H), 8.00 (d, J=7.8 Hz,1H), 7.94-7.87 (m, 1H), 7.78-7.68 (m, 3H), 7.59 (d, J=7.7 Hz, 1H),7.43-7.36 (m, 2H), 7.31-7.15 (m, 2H), 5.76 (s, 1H), 2.31 (t, J=8.2 Hz,2H), 1.07 (dq, J=15.1, 7.5 Hz, 2H), 0.62 (q, J=6.8 Hz, 1H), 0.42-0.22(m, 2H), −0.07 (q, J=4.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.95.

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92f) (300 mg, 0.564 mmol) in methanol (25 mL) at 0° C. was addednickel(II) chloride hexahydrate (29.2 mg, 0.123 mmol), To this sodiumtetrahydroborate (133 mg, 3.53 mmol) was added in small portions over aperiod of 15 minutes. The reaction was stirred for 15 minutes, quenchedby adding N1-(2-aminoethyl)ethane-1,2-diamine (0.135 mL, 1.298 mmol) andstirred for 30 minutes at room temperature. The reaction mixture wasconcentrated in vacuum to remove methanol. The residue was adsorbed onsilicagel and purified twice by flash column chromatography (silica gel,12 g, eluting with CMA 80 in chloroform 0 to 100%) and (silica gel 2×4g, eluting with methanol in chloroform 0 to 30%) to afford1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(92g) (20 mg, 6.62% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.67 (s, 1H, D₂O exchangeable), 8.52-8.41 (m, 2H), 7.70 (s,1H), 7.54 (d, J=15.9 Hz, 3H), 7.49-7.35 (m, 4H), 7.26 (ddd, J=20.1,11.6, 7.3 Hz, 3H), 5.76 (s, 1H, D₂O exchangeable), 3.77 (s, 2H), 2.31(t, J=8.3 Hz, 2H), 2.08 (s, 2H, D₂O exchangeable), 1.06 (dq, J=21.4, 7.4Hz, 2H), 0.63 (t, J=6.7 Hz, 1H), 0.40-0.28 (m, 2H), −0.07 (q, J=4.7 Hz,2H); MS (ES+) 536.2 (M+1), (ES−) 534.2 (M−1); Analysis calculated forC₂₉H₂₈F₃N₅O₅: C: 65.02, H: 5.27, N: 13.08; Found: C, 64.69; H, 5.40: N,13.08.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93a)

To a solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (0.2 g, 0.440 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.096 mL, 1.320 mmol), and allowed to warm to roomtemperature over a period of 3 h. The reaction mixture was treated withmorpholine (1.518 mL, 17.60 mmol) and evaporated to dryness. The residuewas dissolved in N,N dimethyl formamide (20 mL), added morpholine (1.518mL, 17.60 mmol) and heated to reflux for 18 h. Excess solvent waspumped-off under reduced pressure. The residue was diluted with water(30 mL) and extracted with ethyl acetate (2×30 mL). The organic layerswere combined dried over anhydrous MgSO₄, filtered and evaporated todryness. The residue was purified by flash column chromatography [silicagel 25 g, eluting with methanol in chloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93a) (200 mg, 87% yield) as a dark yellow waxy solid; MS (ES+): MS(ES+) 524.3 (M+1), MS (ES−) 522.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93a) (0.192 g, 0.367 mmol) in anhydrous methanol (10 mL) cooled to 0°C., was added nickel(II) chloride hexahydrate (0.131 g, 0.550 mmol)followed by sodium borohydride (0.166 g, 4.40 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 34 min, TLCanalysis (methanol/chloroform, 2/8, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (0.396 mL, 3.67 mmol) wasadded. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL), andproduct was extracted with chloroform (2×30 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered and evaporated to dryness.The residue was purified by flash column chromatography [(silica gel 40g, eluting with methanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(93b) (39 mg, 20% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (d, J=10.1 Hz, 1H, D₂O exchangeable), 7.59 (d, J=7.8 Hz, 2H),7.56-7.52 (m, 1H), 7.45 (ddt, J=5.7, 4.0, 2.1 Hz, 3H), 7.41-7.33 (m,1H), 7.29 (t, J=7.8 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 3.79 (s, 2H), 3.52(t, J=4.7 Hz, 4H), 3.27 (dd, J=8.6, 5.3 Hz, 1H), 2.29 (h, J=7.2, 6.6 Hz,4H), 2.02-1.88 (m, 1H), 1.70 (dtd, J=13.7, 9.3, 5.2 Hz, 1H), 1.07 (ddt,J=12.7, 9.7, 6.2 Hz, 1H), 0.99-0.81 (m, 1H), 0.69-0.54 (m, 1H),0.42-0.24 (m, 2H), −0.09 (td, J=5.4, 3.7 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.73; MS (ES⁺): MS (ES+) 528.3 (M+1), MS (ES−) 526.1 (M−1),562.3 (M+Cl); Analysis calculated for C₂₈H₃₂F₃N₅O₂.0.25H₂O: C, 63.20; H,6.16; N, 13.16; Found: C, 63.23; H, 6.18; N, 12.73.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94b) Step-1: Preparation of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94a)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(48d) (1.433 g, 2.98 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.651 mL, 8.93 mmol) allowed to warm to roomtemperature and stirred for 12 h. The reaction mixture was quenched withcyclopropylmethyl amine (1.275 mL, 14.88 mmol) stirred for 1 h at roomtemperature, and concentrated in vacuum to dryness. The residue wasdissolved in cyclopropylmethyl amine (5.10 mL, 59.5 mmol), acetonitrile(20 mL) and heated at 100° C. for 18 h. TLC analysis (CHCl₃/MeOH, 9/1,v/v) shows reaction was complete, the reaction mixture was evaporated todryness. The residue was purified by flash column chromatography (silicagel 40 g, eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94a) (0.841 g, 53% yield) as an orange red solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.55 (s, 1H, D₂O exchangeable), 8.61 (d, J=2.1 Hz, 1H), 8.40(dd, J=4.8, 1.7 Hz, 1H), 8.13 (t, J=1.7 Hz, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.95-7.86 (m, 1H), 7.80-7.69 (m, 3H), 7.60 (dd, J=7.7, 2.2 Hz,1H), 7.42-7.19 (m, 3H), 4.92 (s, 1H), 2.69 (s, 1H, D₂O exchangeable),2.27 (dd, J=6.7, 2.3 Hz, 2H), 0.90 (ddt, J=7.7, 5.9, 4.6 Hz, 1H),0.44-0.31 (m, 2H), 0.04 (tt, J=5.7, 2.9 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.99, −122.96; IR (KBr, cm⁻¹): 2234 cm⁻¹ (—CN stretching);MS (ES⁺): MS (ES+) 535.2 (M+1), 557.2 (M+Na), MS (ES−) 533.2 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94b)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94a) (0.612 g, 1.145 mmol) in anhydrous methanol (30 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.408 g, 1.717 mmol)followed by sodium borohydride (0.347 g, 9.16 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 min. TLCanalysis (methanol/chloroform, 1/9, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (1.237 mL, 11.45 mmol)was added. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (50 mL), andproduct was extracted with chloroform (2×50 mL). The organic layers werecombined organic layer, dried over MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography[(silica gel 40 g, eluting with methanol/chloroform from 0 to 50%)] tofurnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(94b) (258 mg, 42% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H, D₂O exchangeable), 8.60 (d, J=2.2 Hz, 1H), 8.40 (dd,J=4.7, 1.7 Hz, 1H), 7.77 (dt, J=7.9, 2.0 Hz, 1H), 7.65 (dd, J=7.5, 2.2Hz, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.47-7.41 (m, 2H), 7.39-7.29 (m,3H), 7.23 (dd, J=10.3, 8.5 Hz, 2H, 1H D₂O exchangeable), 4.91 (s, 1H),3.78 (s, 2H), 2.27 (dd, J=6.5, 2.5 Hz, 2H), 0.97-0.84 (m, 1H), 0.44-0.32(m, 2H), 0.08-0.01 (m, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 8.59 (d,J=2.2 Hz, 1H), 8.40 (dd, J=4.8, 1.6 Hz, 1H), 7.79 (dt, J=8.1, 2.0 Hz,1H), 7.65 (dd, J=7.4, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J=2.1 Hz, 1H),7.45 (dd, J=4.7, 2.5 Hz, 2H), 7.34 (tt, J=4.8, 2.8 Hz, 3H), 7.23 (dd,J=10.3, 8.6 Hz, 1H), 4.92 (s, 1H), 3.76 (s, 2H), 2.26 (dd, J=6.9, 1.7Hz, 2H), 1.03-0.76 (m, 1H), 0.48-0.30 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.76, −123.40; MS (ES⁺): MS (ES+) 539.2(M+1), MS (ES−) 537.2 (M−1); Analysis calculated for:C₂₈H₂₆F₄N₆O.0.25H₂O: C, 61.93; H, 4.92; N, 15.48; Found: C, 61.73; H,5.06; N, 15.16.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95i)Step-1: Preparation of 3-Bromo-N-methoxy-N-methyl-5-nitrobenzamide (95b)

To a solution of 3-bromo-5-nitrobenzoic acid (95a) (5 g, 20.32 mmol) intoluene (40 mL) was added thionyl chloride (14.83 mL, 203 mmol) andheated at reflux for 1 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in CH₂Cl₂ (40.0mL) and added N,O-dimethylhydroxylamine hydrochloride (2.97 g, 30.5mmol) followed by triethylamine (14.16 mL, 102 mmol). The reactionmixture was stirred at room temperature overnight, washed with 1 N HCl(40 mL), 1 N NaOH (40 mL), water (40 mL), brine (40 mL), dried filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish3-bromo-N-methoxy-N-methyl-5-nitrobenzamide (95b) (4.5 g, 15.57 mmol,77% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (t, J=2.0Hz, 1H), 8.37 (dd, J=2.1, 1.4 Hz, 1H), 8.23 (dd, J=1.8, 1.4 Hz, 1H),3.57 (s, 3H), 3.31 (s, 3H).

Step-2: Preparation of 3-cyclopropyl-N-methoxy-N-methyl-5-nitrobenzamide(95c)

To a 250 mL single-neck flask with a magnetic stir bar was charged with3-bromo-N-methoxy-N-methyl-5-nitrobenzamide (95b) (2.394 g, 8.28 mmol),cyclopropylboronic acid (1.423 g, 16.56 mmol), potassium phosphatemonohydrate (4.77 g, 20.70 mmol), tricyclohexylphosphine (0.697 g, 2.484mmol) and palladium(II) acetate trimer (0.837 g, 1.242 mmol). The flaskwas degassed and purged with nitrogen, this cycle was repeated twice,and then the reaction mixture was diluted with toluene (30 mL) and water(10 mL). The reaction mixture was again degassed and purged withnitrogen twice, and then the reaction mixture was purged with nitrogenfor 5 min and started heating to reflux at 120° C. and stirred for 50 h,TLC analysis (ethyl acetate/hexanes, 3/7, v/v) shows reaction wascomplete. The reaction mixture was cooled to room temperature, quenchedwith water (50 mL) and extracted with ethyl acetate (3×75 mL). Theorganic layers were combined washed with brine (50 mL), dried overanhydrous MgSO₄ (10 g), filtered and excess solvent was removed underreduced pressure. The residue and was purified by flash columnchromatography (40 g silica gel, eluting with ethyl acetate in hexanesfrom 0-50%) to furnish 3-cyclopropyl-N-methoxy-N-methyl-5-nitrobenzamide(95c) (1.523 g, 73% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (dd, J=2.2, 1.4 Hz, 1H), 8.03 (t, J=2.0 Hz, 1H), 7.71(t, J=1.6 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H), 2.20 (tt, J=8.3, 5.0 Hz,1H), 1.14-1.03 (m, 2H), 0.85 (dt, J=6.9, 4.6 Hz, 2H); MS (ES⁺): MS (ES+)251.1 (M+1), 273.1 (M+Na).

Step-3: Preparation of 3-Amino-5-cyclopropyl-N-methoxy-N-methylbenzamide(95d)

To a stirred solution of3-cyclopropyl-N-methoxy-N-methyl-5-nitrobenzamide (95c) (1.2 g, 4.80mmol) in anhydrous methanol (25 mL), cooled to 0° C., was addednickel(II) chloride hexahydrate (285 mg, 1.199 mmol) followed by sodiumborohydride (499 mg, 13.19 mmol) portionwise over a 30 mins period. Thereaction mixture was stirred for 15 min at room temperature. Thereaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine(1.036 mL, 9.59 mmol), stirred for 30 minutes and concentrated in vacuumto dryness. The residue was dissolved in ethyl acetate (25 mL), washedwith water (25 mL), brine (25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 12 g, eluting with ethyl acetate/hexanes from 0 to 100%) tofurnish 3-Amino-5-cyclopropyl-N-methoxy-N-methylbenzamide (95d) (0.875g, 3.97 mmol, 83% yield) as a yellow semisolid; ¹H NMR (300 MHz,DMSO-d₆) δ 6.50 (dd, J=2.2, 1.5 Hz, 1H), 6.38 (t, J=1.6 Hz, 1H), 6.34(t, J=1.9 Hz, 1H), 5.15 (s, 2H), 3.54 (s, 3H), 3.18 (s, 3H), 1.78 (tt,J=8.4, 5.0 Hz, 1H), 0.95-0.82 (m, 2H), 0.67-0.48 (m, 2H); MS (ES+) 221.1(M+1), 243.1 (M+Na).

Step-4: Preparation of (3-Amino-5-cyclopropylphenyl)(phenyl)methanone(95e)

To a stirred solution of3-amino-5-cyclopropyl-N-methoxy-N-methylbenzamide (95d) (0.875 g, 3.97mmol) in anhydrous THF (15 mL), cooled to 0° C., was added dropwisephenylmagnesium bromide (8.94 mL, 8.94 mmol). The reaction mixture wasstirred at room temperature for 3 h, quenched and with saturated aqueousNH₄Cl (25 mL). The reaction mixture was extracted with ethyl acetate(2×25 mL). The organic layers were combined washed brine (25 mL), dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel 12 g, eluting with ethylacetate/hexanes from 0 to 100%)] to furnish(3-amino-5-cyclopropylphenyl)(phenyl)methanone (95e) (0.15 g, 15.91%) asan yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.73-7.61 (m, 3H), 7.58-7.51(m, 2H), 6.70 (dd, J=2.2, 1.5 Hz, 1H), 6.58 (t, J=1.6 Hz, 1H), 6.52 (t,J=1.9 Hz, 1H), 5.31 (s, 2H), 1.84 (tt, J=8.3, 5.0 Hz, 1H), 0.96-0.82 (m,2H), 0.69-0.52 (m, 2H); MS (ES+) 238.2 (M+1), 260.1 (M+Na); (ES−) 306.1(M−1).

Step-5: Preparation of (3-Amino-5-cyclopropylphenyl)(phenyl)methanol(95f)

To a stirred solution of (3-amino-5-cyclopropylphenyl)(phenyl)methanone(95e) (0.15 g, 0.632 mmol) in methanol (5 mL), cooled to 0° C., wasadded sodium borohydride (120 mg, 3.16 mmol) portionwise over a 10 minsperiod. The reaction mixture was stirred for 5 min at room temperatureand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 12 g, eluting with 9:1 ethylacetate/methanol in hexanes from 0 to 100%)] to furnish(3-amino-5-cyclopropylphenyl)(phenyl)methanol (95f) (0.099 g, 0.414mmol, 65.4% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.35-7.23 (m, 4H), 7.23-7.14 (m, 1H), 6.33 (t, J=1.8 Hz, 1H), 6.31 (d,J=1.6 Hz, 1H), 6.06 (t, J=1.9 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 5.44 (d,J=3.9 Hz, 1H), 4.88 (s, 2H), 1.70 (tt, J=8.4, 5.1 Hz, 1H), 0.89-0.77 (m,2H), 0.58-0.39 (m, 2H); MS (ES+) 240.2 (M+1); (ES−) 238.1 (M−1).

Step-6: Preparation of1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95g)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.134 g, 0.476 mmol) in DMF (5 mL) was added(3-amino-5-cyclopropylphenyl)(phenyl)methanol (95f) (0.095 g, 0.397mmol), N-ethyl-N-isopropylpropan-2-amine (0.346 mL, 1.985 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop, 0.222 g,0.476 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 37 h under nitrogen atmosphere. The reaction wasdiluted with water (25 mL) and extracted with ethyl acetate (2×25 mL).The combined organic layer was washed with brine (25 mL), dried,filtered, and evaporated to dryness. The residue obtained was purifiedby flash column chromatography [silica gel 24 g, eluting with ethylacetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95g) (0.184 g, 0.366 mmol, 92% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7,1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H),7.70 (d, J=2.6 Hz, 1H), 7.41 (t, J=1.8 Hz, 1H), 7.36-7.25 (m, 4H),7.25-7.15 (m, 2H), 6.92 (t, J=1.5 Hz, 1H), 5.89 (d, J=3.8 Hz, 1H), 5.61(d, J=3.7 Hz, 1H), 1.93-1.80 (m, 1H), 0.99-0.82 (m, 2H), 0.63-0.51 (m,2H); 19F NMR (282 MHz, DMSO) δ −60.99. MS (ES+) 525.2 (M+Na), (ES−)501.1 (M−1).

Step-7: Preparation of1-(3-Cyanophenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95h)

To a solution of1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95g) (0.18 g, 0.358 mmol) in dichloromethane (10 mL) at 0⁰c was addedthionyl chloride (0.065 mL, 0.896 mmol) and allowed to warm to roomtemperature over 3 h. The reaction mixture was quenched withcyclopropylmethanamine (0.078 mL, 0.896 mmol), stirred for 2 h at roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in acetonitrile (2.5 mL) and added cyclopropylmethanamine(0.777 mL, 8.96 mmol). The reaction mixture was heated at refluxovernight, cooled to room temperature concentrated in vacuum to dryness.The residue obtained was dissolved in chloroform (25 mL), washed withwater (10 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel 12 g,eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95h) (0.122 g, 0.220 mmol, 61.3% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8,1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H),7.70 (d, J=2.1 Hz, 1H), 7.45 (t, J=1.7 Hz, 1H), 7.42-7.35 (m, 2H), 7.28(t, J=7.5 Hz, 2H), 7.23-7.13 (m, 2H), 7.00-6.94 (m, 1H), 4.76 (s, 1H),2.27 (s, 2H), 1.85 (td, J=8.4, 4.3 Hz, 1H), 0.97-0.87 (m, 3H), 0.60-0.54(m, 2H), 0.42-0.33 (m, 2H), 0.08-0.00 (m, 2H); 19F NMR (282 MHz, DMSO) δ−60.98; MS (ES+) 556.2 (M+1); (ES−) 554.3 (M−1).

Step-8: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95i)

To a stirred solution of1-(3-cyanophenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95h) (0.12 g, 0.216 mmol) in anhydrous methanol (10 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (0.064 g, 0.270 mmol),Sodium borohydride (0.065 g, 1.728 mmol) was added to the reactionmixture in small portions over a 15 min period. The reaction mixture wasstirred for 15 min at 0° C. and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.07 mL, 0.648 mmol) stirred for 30mins and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (25 mL) and water (25 mL). The organiclayer was separated, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel12 g, eluting with 0-25% methanol in chloroform) to furnish1-(3-(aminomethyl)phenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(95i) (0.044 g, 0.079 mmol, 36.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.57 (s, 1H), 7.55 (s, 1H), 7.51 (d, J=2.2 Hz, 1H),7.47-7.36 (m, 5H), 7.33-7.23 (m, 3H), 7.22-7.14 (m, 2H), 6.99-6.93 (m,1H), 4.76 (s, 1H), 3.78 (s, 2H), 2.25 (t, J=8.7 Hz, 4H), 1.85 (tt,J=8.4, 5.0 Hz, 1H), 0.99-0.83 (m, 3H), 0.63-0.51 (m, 2H), 0.48-0.31 (m,2H), 0.10-−0.01 (m, 2H); MS (ES−) 558.3 (M−1).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96f) Step-1: Preparation of(4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol (96b)

To a solution of 3-bromopyridine (2.60 mL, 26.9 mmol) in ether (20 mL)at −78° C. was added dropwise n-BuLi (14.31 mL, 22.90 mmol) and stirredfor 30 mins at −78° C. To the 3-lithiated pyridine was added dropwise asolution of 4-chloro-3-nitrobenzaldehyde (96a) (5.00 g, 26.9 mmol) inTHF (30 mL) at −78° C. and stirred at −78° C. for 2 h and at roomtemperature for 2 h. The reaction mixture was quenched with saturatedammonium chloride (50 mL). The organic layer was separated, dried,filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 80 g, eluting with0-100% ethyl acetate in hexane) to afford(4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol (96b) (1.5 g, 5.67 mmol,21.03% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.66-8.62 (m,1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H), 8.17-8.11 (m, 1H), 7.79-7.70 (m, 3H),7.36 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 6.47 (d, J=4.1 Hz, 1H), 5.93 (d,J=4.1 Hz, 1H); MS (ES+) 265.1 (M+1), (ES−) 263.1 (M−1).

Step-2: Preparation of (3-amino-4-chlorophenyl)(pyridin-3-yl)methanol(96c)

To a stirred solution of (4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol(96b) (1.5 g, 5.67 mmol) in anhydrous methanol (25 mL), cooled to 0° C.,was added nickel(II) chloride hexahydrate (0.337 g, 1.417 mmol) followedby sodium borohydride (0.643 g, 17 mmol) portionwise over a 30 minsperiod. The reaction mixture was stirred for 15 min at room temperature.The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.225 mL, 11.34 mmol) stirred for30 minutes and concentrated in vacuum to dryness. The residue wasdissolved in ethyl acetate (25 mL), washed with water (25 mL), brine (25mL), dried, filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, elutingwith ethyl acetate/hexanes from 0 to 100%)] to furnish(3-amino-4-chlorophenyl)(pyridin-3-yl)methanol (96c) (0.119 g, 0.507mmol, 8.95% yield) as a oil, which was pure enough to be taken to nextstep; MS (ES+) 235.1 (M+1).

Step-3: Preparation ofN-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96d)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.463 g, 1.648 mmol) in DMF (10 mL) was added(3-amino-4-chlorophenyl)(pyridin-3-yl)methanol (96c) (0.826 g, 3.52mmol), N-ethyl-N-isopropylpropan-2-amine (3.07 mL, 17.6 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 1.969 g,4.22 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (25 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic layer was washed with brine (50 mL), dried, filtered,and evaporated to dryness. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting with ethyl acetate inhexanes from 0-100%) to furnishN-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96d) (0.328 g, 0.659 mmol, 18.72% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.61-8.56 (m, 1H), 8.44 (dd, J=4.7, 1.7Hz, 1H), 8.12 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.95-7.88 (m, 1H),7.75 (d, J=8.0 Hz, 1H), 7.70 (d, J=3.6 Hz, 2H), 7.55 (s, 1H), 7.51 (d,J=8.3 Hz, 1H), 7.37-7.34 (m, 1H), 7.34-7.31 (m, 1H), 6.26 (d, J=4.1 Hz,1H), 5.81 (d, J=4.0 Hz, 1H); 19F NMR (282 MHz, DMSO) δ −60.98; MS (ES+)498.1 (M+1); (ES−) 496.0 (M−1).

Step-4: Preparation ofN-(2-Chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96e)

To a solution ofN-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96d) (0.328 g, 0.659 mmol) in dichloromethane (10 mL) at 0° C. wasadded thionyl chloride (0.144 mL, 1.976 mmol) and allowed to warm toroom temperature over 3 h. The reaction mixture was quenched withcyclopropylmethanamine (0.171 mL, 1.976 mmol), stirred for 2 h at roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in acetonitrile (5 mL) and added cyclopropylmethanamine (1.429mL, 16.47 mmol). The reaction mixture was heated at reflux overnight,cooled to room temperature concentrated in vacuum to dryness. Theresidue obtained was dissolved in chloroform (25 mL), washed with water(10 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel 24 g,eluting 0-100% ethyl acetate/methanol 9:1 in hexane) to affordN-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96e) (0.2 g, 0.363 mmol, 55.1% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.45-8.37 (m,1H), 8.11 (d, J=2.1 Hz, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H), 7.92 (d,J=8.3 Hz, 1H), 7.75 (dd, J=15.6, 7.6 Hz, 3H), 7.60 (s, 1H), 7.49 (d,J=8.3 Hz, 1H), 7.41 (dd, J=8.4, 2.0 Hz, 1H), 7.32 (dd, J=7.8, 4.8 Hz,1H), 4.94 (s, 1H), 2.27 (d, J=6.3 Hz, 2H), 0.97-0.82 (m, 1H), 0.43-0.32(m, 2H), 0.15-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.98; MS (ES+)551.2 (M+1); (ES−) 549.2 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96f)

To a stirred solution ofN-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96e) (0.2 g, 0.363 mmol) in anhydrous methanol (10 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (0.108 g, 0.454 mmol),Sodium borohydride (0.11 g, 2.9 mmol) was added to the reaction mixturein small portions over a 15 min period. The reaction mixture was stirredfor 15 min at 0° C. and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.12 mL, 1.1 mmol) stirred for 30mins and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (25 mL) and water (25 mL). The organiclayer was separated, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel12 g, eluting with 0-25% methanol in chloroform) to furnish1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(96f) (0.040 g, 0.072 mmol, 19.85% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.38 (s, 1H), 8.67-8.55 (m, 1H), 8.41 (dd, J=4.8, 1.6Hz, 1H), 7.77 (dt, J=8.0, 1.9 Hz, 1H), 7.66-7.54 (m, 3H), 7.51-7.36 (m,5H), 7.35-7.28 (m, 1H), 4.93 (s, 1H), 3.87 (s, 2H), 2.27 (d, J=6.6 Hz,2H), 0.97-0.81 (m, 1H), 0.42-0.31 (m, 2H), 0.11-−0.02 (m, 2H); 19F NMR(282 MHz, DMSO) δ −60.77; MS (ES+) 555.2 (M+1); 553.2 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97f) Step-1: Preparation of3-fluoro-N-methoxy-N-methyl-5-nitrobenzamide (97a)

To a suspension of 3-fluoro-5-nitrobenzoic acid (80a) (2.5 g, 13.51mmol) in toluene (10 mL) was added thionyl chloride (9.86 mL, 135 mmol)three drops of DMF, heated at reflux for 1 h and evaporated in vacuum todryness. To this residue was added dichloromethane (10 mL),N,O-dimethylhydroxylamine hydrochloride (1.976 g, 20.26 mmol) and cooledto 0° C. To the solution was added triethylamine (TEA) (9.41 mL, 67.5mmol) and stirred at room temperature for 16 h. Excess solvent waspumped-off under reduced pressure. The residue was treated with water(75 mL), extracted with ethyl acetate (100 mL, 75 mL). The combinedorganics were dried over MgSO₄ filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 40 g,eluting with ethyl acetate in hexanes from 0-100%)] furnish (97a) (2.039g, 66% yield) as light yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.31-8.23(m, 2H), 7.97 (ddd, J=8.6, 2.4, 1.4 Hz, 1H), 3.58 (s, 3H), 3.31 (s, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −109.15; MS (ES⁺): MS (ES+) 229.10 (M+1),251.1 (M+Na).

Step-2: Preparation of 3-amino-5-fluoro-N-methoxy-N-methylbenzamide(97b)

To a solution of 3-fluoro-N-methoxy-N-methyl-5-nitrobenzamide (97a) (2g, 8.77 mmol) in methanol (30 mL) was added palladium (10% Pd on carbon)(0.187 g, 1.753 mmol). The reaction mixture was hydrogenated at 60 psifor 3 h. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) shows reactionwas complete. The reaction was filtered through a small Celite© pad,Celite© pad was subsequently washed with methanol (2×25 mL), and ethylacetate (25 mL). Excess solvents were pumped-off under reduced pressure.The residue was purified by flash column chromatography [(silica gel 80g, eluting with ethyl acetate in hexanes from 0 to 100%)] to afford3-amino-5-fluoro-N-methoxy-N-methylbenzamide (97b) (1.624 g, 93% yield)as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 6.60-6.54 (m, 1H),6.46-6.42 (m, 1H), 6.41-6.37 (m, 1H), 5.63 (s, 2H, D₂O exchangeable),3.56 (s, 3H), 3.21 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −113.68; MS(ES⁺): MS (ES+) 199.1 (M+1), 221.1 (M+Na), MS (ES−) 197.1 (M−1).

Step-3: Preparation of (3-amino-5-fluorophenyl)(phenyl)methanone (97c)

To a solution of 3-amino-5-fluoro-N-methoxy-N-methylbenzamide (97b) (1.6g, 8.07 mmol) in THF (30 mL) cooled to 0° C. was added dropwisephenylmagnesium bromide (16.39 mL, 16.39 mmol) carefully in a positiveflow of nitrogen. The reaction mixture was warmed to room temperatureand for 16 h. The reaction was quenched with saturated aqueous NH₄Cl (60mL), product was extracted with ethyl acetate (100 mL, 75 mL). Thecombined extracts were dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue was purified by flash columnchromatography [(silica gel 80 g, eluting with ethyl acetate in hexanesfrom 0 to 100%)] to afford (3-amino-5-fluorophenyl)(phenyl)methanone(97c) (0.338 g, 19% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.77-7.70 (m, 2H), 7.69-7.64 (m, 1H), 7.56 (tt, J=6.7, 1.5Hz, 2H), 6.74 (t, J=1.7 Hz, 1H), 6.63-6.51 (m, 2H), 5.79 (s, 2H, D₂Oexchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.89; MS (ES⁺): MS (ES+)216.1 (M+1), MS (ES−) 214.1 (M−1).

Step-4: Preparation ofN-(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97d)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.510 g, 1.812 mmol), (3-amino-5-fluorophenyl)(phenyl)methanone (97c)(0.325 g, 1.510 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (0.845 g, 1.812 mmol) was addedN,N-dimethylformamide (9 mL) and N-ethyl-N-isopropylpropan-2-amine(1.315 mL, 7.55 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under nitrogen atmosphere. Excess DMF waspumped-off under reduced pressure. The reaction was diluted with water(50 mL) and extracted with ethyl acetate (2×50 mL); the combined organiclayer was dried over anhydrous MgSO₄, filtered, and evaporated todryness. The residue was purified by flash column chromatography [silicagel 25 g, eluting with ethyl acetate in hexanes from 0-100%] to furnishN-(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97d) (0.584 g, 1.221 mmol, 81% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.04 (s, 1H, D₂O exchangeable), 8.21 (t, J=1.9 Hz, 1H),8.02 (dt, J=7.7, 1.3 Hz, 1H), 7.98-7.89 (m, 2H), 7.83-7.69 (m, 6H),7.64-7.55 (m, 2H), 7.31 (ddd, J=8.7, 2.5, 1.3 Hz, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −61.00, −110.34; MS (ES⁺): MS (ES+) 479.2 (M+1), MS (ES−)512.8 (M+Cl), 955.2 (2M−1).

Step-5: Preparation of tert-butyl 3-(5-(3-fluoro-5-(hydroxy (phenyl)methyl) phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (97e)

To a stirred solution ofN-(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97d) (0.558 g, 1.166 mmol) in anhydrous methanol (20 mL), cooled to 0°C. was added di-tert-butyl dicarbonate (0.764 g, 3.50 mmol), nickel(II)chloride hexahydrate (0.069 g, 0.292 mmol) followed by sodiumborohydride (0.265 g, 7.00 mmol) in small portions over a period of 5min. The reaction mixture was additionally stirred for 15 min, TLCanalysis (ethyl acetate/hexanes, 3/7, v/v) shows reaction was completeat this point N1-(2-aminoethyl) ethane-1; 2-diamine (0.252 mL, 2.333mmol) was added. The mixture was allowed to stir for 30 minutes andsolvent was evaporated under vacuum. The residue was treated with water(25 mL), and extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried over MgSO₄; filtered and excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography [(silica gel 25 g, eluting with ethylacetate/hexanes from 0 to 100%)] to furnish tert-butyl3-(5-(3-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(97e) (0.317 g, 46.5% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.87 (s, 1H, D₂O exchangeable), 7.60 (s, 1H), 7.56-7.44 (m,2H), 7.43-7.27 (m, 9H), 7.27-7.19 (m, 1H), 6.99 (dt, J=9.6, 1.8 Hz, 1H),6.08 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.68 (d, J=3.8 Hz, 1H), 4.19(d, J=6.3 Hz, 2H), 1.35 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.84,−112.19; MS (ES⁺): MS (ES+) 607.2 (M+Na), MS (ES−) 583.2 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97f)

To a solution of tert-butyl3-(5-(3-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(97e) (301 mg, 0.515 mmol) in 1,4-dioxane (5 mL) was added hydrogenchloride (4 M in 1,4-dioxane, 7.47 mL, 29.9 mmol) and stirred at roomtemperature for 14 h. The reaction was concentrated in vacuum to drynessand the residue was purified by flash column chromatography [(silica gel25 g, eluting with CMA80 in chloroform from 0-100%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97f) (0.177 g, 71% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.88 (s, 1H, D₂O exchangeable), 7.63 (s, 1H), 7.60 (s, 1H), 7.52-7.47(m, 2H), 7.46-7.40 (m, 2H), 7.39-7.28 (m, 5H), 7.26-7.19 (m, 1H), 6.99(d, J=9.5 Hz, 1H), 6.09 (s, 1H, D₂O exchangeable), 5.68 (s, 1H), 3.94(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −112.18; MS (ES⁺): MS(ES+) 485.2 (M+1), 969.3 (2M+1), MS (ES−) 483.1 (M−1), 519.2 (M+Cl),967.3 (2M−1).

Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98a)

To a solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (0.261 g, 0.574 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.126 mL, 1.723 mmol) and allowed to warm toroom temperature over a period of 3 h. The reaction mixture wasconcentrated in vacuum. The residue was dissolved in N,N dimethylformamide (20 mL) and added pyrrolidine (1.918 mL, 22.97 mmol). Thereaction was heated at reflux for 18 h. TLC analysis shows reaction wascomplete. Excess solvent was pumped-off under reduced pressure. Theresidue was diluted with water (30 mL) and extracted with ethyl acetate(2×30 mL). The combined organic layers were dried over anhydrous MgSO₄,filtered and evaporated to dryness. The residue was purified by flashcolumn chromatography [silica gel 25 g, eluting with methanol inchloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98a) (97 mg, 33% yield) as a white waxy solid. MS (ES⁺): MS (ES+) 508.2(M+1), MS (ES−) 542.2 (M+Na); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.96.

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98a) (0.091 g, 0.179 mmol) in anhydrous methanol (20 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.064 g, 0.269 mmol)followed by sodium borohydride (0.054 g, 1.434 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 min, TLCanalysis (methanol/chloroform, 1/9, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (0.194 mL, 1.793 mmol)was added. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL), andproduct was extracted with chloroform (2×30 mL). The combined organiclayers were dried over MgSO₄, filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 25 g,eluting with methanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(98b) (52 mg, 57% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H, D₂O exchangeable), 7.65-7.49 (m, 4H), 7.48-7.42 (m, 2H),7.34 (dt, J=6.2, 2.5 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz,1H), 3.79 (s, 2H), 3.07 (dd, J=9.4, 3.9 Hz, 1H), 2.27 (s, 3H), 1.92 (s,1H), 1.64 (d, J=6.1 Hz, 6H), 0.97 (d, J=10.5 Hz, 1H), 0.79 (s, 1H), 0.58(s, 1H), 0.32 (dd, J=8.2, 1.5 Hz, 2H), −0.08-−0.18 (m, 2H); ¹H NMR (300MHz, DMSO-d₆ D₂O) δ 7.63-7.41 (m, 6H), 7.34 (dt, J=5.3, 2.5 Hz, 1H),7.27 (t, J=7.8 Hz, 1H), 7.03 (dt, J=7.7, 1.3 Hz, 1H), 3.77 (s, 2H), 3.07(dd, J=9.7, 4.0 Hz, 1H), 2.28 (d, J=7.7 Hz, 2H), 1.94 (t, J=12.0 Hz,1H), 1.64 (q, J=6.4, 5.4 Hz, 5H), 0.98 (dt, J=16.5, 6.8 Hz, 1H), 0.77(s, 1H), 0.58 (p, J=5.9 Hz, 1H), 0.43-0.24 (m, 2H), −0.05-−0.22 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73 (d, J=4.5 Hz); MS (ES+): MS (ES+)512.3 (M+1), MS (ES−) 510.2 (M−1); Analysis calculated for:C₂₈H₃₂F₃N₅O.0.25H₂O: C, 65.16; H, 6.35; N, 13.57; Found: C, 64.92; H,6.24; N, 13.21.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-(cyclopropylamino)-1-hydroxy-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(99g) Step-1: Preparation of 2-(cyclopropylamino)-1-phenylethanone (99b)

To a stirred solution of 2-bromo-1-phenylethanone (99a) (4 g, 20.10mmol) in acetonitrile (50 mL) was added cyclopropylamine (2.83 mL, 40.2mmol) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The crude reaction mixture was usedas such for next step.

Step-2: Preparation of tert-butylcyclopropyl(2-oxo-2-phenylethyl)carbamate (99c)

To the solution from Step-1 of 2-(cyclopropylamino)-1-phenylethanone(99b) (3.50 g, 20 mmol) in acetonitrile at 0° C. was added triethylamine(11.15 mL, 80 mmol) and (Boc)₂₀ (4.64 mL, 20.00 mmol). The reactionmixture was stirred for 2 h at room temperature and diluted with water(100 mL). The reaction was extracted with dichloromethane (2×150 mL).The combined organic layer were washed with water (2×50 mL), brine (50mL) dried and concentrated in vacuum. The crude residue was purified byflash column chromatography (silica gel, 80 g eluting with ethyl acetatein hexanes 0 to 50 to 100%) to afford tert-butyl cyclopropyl(2-oxo-2phenylethyl)carbamate (99c) (5.5 g, 100%) as a white semisolid; MS (ES+)298.2 (M+Na).

Step-3: Preparation of tert-butyl2-(3-aminophenyl)-2-hydroxy-2-phenylethyl(cyclopropyl) carbamate (99d)

To a stirred solution of tert-butylcyclopropyl(2-oxo-2-phenylethyl)carbamate (99c) (1 g, 3.63 mmol) intetrahydrofuran (25 mL) cooled to at 0° C. was added(3-(bis(trimethylsilyl)amino) phenyl)magnesium bromide (49c) (4.0 mL,4.0 mmol). The reaction was allowed to warm to room temperature, stirredfor 2 h and quenched by adding ammonium chloride solution (50 mL). Thereaction was stirred for 1 h and extracted with ethyl acetate (2×100mL). The combined organic layer was washed with water (2×50 mL), brine(50 mL), dried, and filtered concentrated in vacuum. The crude residuewas purified by flash column chromatography (silica gel 40 g, elutingwith ethyl acetate in hexanes 0 to 40% to 100%) to afford tert-butyl2-(3-aminophenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate (99d)(460 mg, 34.4%) as a white semisolid; MS (ES+) 391.2 (M+Na), (759.4)(2M+Na).

Step-4: Preparation of tert-butyl2-(3-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99e)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.268 g, 0.954 mmol) in N,N-dimethylformamide (5.76 mL, 74.4 mmol) wasadded tert-butyl2-(3-aminophenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate (99d)(0.422 g, 1.145 mmol), N-ethyl-N-isopropylpropan-2-amine (1.334 mL, 7.64mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP,0.489 g, 1.05 mmol) at room temperature. The resulting reaction mixturewas stirred at 25° C. for 16 h. The reaction mixture was diluted withwater (50 mL). The solid separated was collected by filtration, dried invacuum and purified by flash column chromatography (silica gel 12 g,eluting with CMA 80 in chloroform 0-100%) to furnish tert-butyl2-(3-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99e) (507 mg, 0.803 mmol, 84% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.65 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H),7.70 (d, J=3.0 Hz, 2H), 7.62 (dd, J=7.7, 1.9 Hz, 1H), 7.43 (d, J=7.6 Hz,2H), 7.33-7.25 (m, 3H), 7.24-7.18 (m, 2H), 5.76 (s, 1H), 4.13-4.00 (m,2H), 2.27 (s, 1H), 1.21 (s, 9H), 0.50 (d, J=7.2 Hz, 2H), 0.44 (d, J=4.1Hz, 2H); MS (ES+) 632.3 (M+1), (ES−) 630. 2 (M−1).

Step-5: Preparation of tert-butyl2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99f)

To a stirred solution of tert-butyl2-(3-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99e) (460 mg, 0.728 mmol) in methanol (50 mL) cooled to 0° C. was addednickel(II) chloride hexahydrate (43.3 mg, 0.182 mmol) followed by sodiumborohydride (220 mg, 5.83 mmol) in small portions over a period of 15minutes. Reaction was stirred at cooled to 0° C. for another 15 minutesquenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.787 mL, 7.28 mmol)and stirred for 30 minutes. Reaction was concentrated in vacuum todryness, diluted with ethyl acetate (50 mL). Ethyl acetate layer waswashed with water (50 mL), brine (20 mL), dried and concentrated invacuum. The crude residue was purified by flash column chromatography(silica gel, 12 g, eluting with CMA 80 in chloroform) to affordtert-butyl2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99f) (0.1 g, 21%) as a white foam; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69(s, 1H), 7.68 (s, 1H), 7.62-7.57 (m, 1H), 7.54 (s, 1H), 7.51 (s, 1H),7.46-7.39 (m, 4H), 7.34-7.23 (m, 4H), 7.23-7.17 (m, 2H), 5.74 (s, 1H),4.04 (q, J=14.1 Hz, 2H), 2.26-2.04 (m, 1H), 1.21 (s, 9H), 0.47 (m, 4H);MS (ES+) 636.3 (M+1); (ES−) 634.2 (M−1).

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-(cyclopropylamino)-1-hydroxy-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(99g)

To a stirred solution of tert-butyl2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate(99f) (125 mg, 0.197 mmol) in 1,4-Dioxane (5 mL) was added hydrochloricacid (4 N in 1,4-dioxane, 2.655 mL, 10.62 mmol) at room temperature andstirred overnight at room temperature. Reaction was concentrated, andpurified by flash column chromatography (silica gel, 12g eluting withCMA 80 in chloroform 0-25%) to afford compound (99g) which wasrepurified by flash column chromatography (silica gel 2×4 g, elutingwith CMA 80 in chloroform 0-100%) to afford1-(3-(aminomethyl)phenyl)-N-(3-(2-(cyclopropylamino)-1-hydroxy-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(99g) (80 mg, 70.3%) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H, D₂O exchangeable), 7.68 (t, J=2.0 Hz, 1H), 7.53 (dd,J=11.7, 3.1 Hz, 3H), 7.45-7.38 (m, 4H), 7.34-7.21 (m, 4H), 7.17 (q,J=7.2, 5.8 Hz, 2H), 5.50 (s, 1H, D₂O exchangeable), 3.77 (s, 2H), 3.31(s, 2H), 2.04 (tt, J=6.7, 3.6 Hz, 1H), 0.31 (td, J=6.3, 3.8 Hz, 2H),0.18 (p, J=3.8 Hz, 2H); MS (ES+) 536.2 (M+1); Analysis calculated forC₂₉H₂₈F₃N₅O₂: C, 65.02; H, 5.27; N, 13.08; Found: C, 64.85; H, 5.37; N,12.74.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100e) Step-1: Preparation of(4-Fluoro-3-nitrophenyl)(pyridin-2-yl)methanol (100a)

To a solution of 4-fluoro-3-nitrobenzaldehyde (48a) (2.1 g, 12.42 mmol)in tetrahydrofuran (50 mL) cooled to 0° C. was addedpyridin-2-ylmagnesium bromide (2.264 g, 12.42 mmol), stirred at 0° C.for 3 h and at room temperature for 14 h, TLC analysis (ethylacetate/hexanes, 1/1, v/v) shows reaction was complete. The reactionmixture was quenched with saturated aqueous NH₄Cl (60 mL), extractedwith EtOAc (2×75 mL). The combined extracts were washed with brine (50mL), dried over anhydrous MgSO₄, filtered, and evaporated to dryness.The residue was purified by flash column chromatography [(silica gel 40g, eluting with ethyl acetate/hexanes from 0 to 50%)] to furnish(4-Fluoro-3-nitrophenyl)(pyridin-2-yl)methanol (100a) (0.366 g, 12%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (ddd, J=4.8,1.8, 0.9 Hz, 1H), 8.18 (ddd, J=7.4, 2.3, 0.7 Hz, 1H), 7.87-7.77 (m, 2H),7.66-7.48 (m, 2H), 7.27 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 6.50 (d, J=4.5Hz, 1H), 5.85 (d, J=4.5 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −121.56;MS (ES⁺): MS (ES+) 271.0 (M+Na), MS (ES−) 247.1 (M−1), 495.1 (2M−1).

Step-2: Preparation of (3-Amino-4-fluorophenyl)(pyridin-2-yl)methanol(100b)

To a stirred solution of (4-fluoro-3-nitrophenyl)(pyridin-2-yl)methanol(100a) (1.345 g, 5.42 mmol) in anhydrous methanol (30 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.322 g, 1.355 mmol)followed by sodium borohydride (0.615 g, 16.26 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 20 min at0° C. TLC analysis (methanol/chloroform, 2/8, v/v) shows reaction wascomplete at this point N1-(2-aminoethyl)ethane-1,2-diamine (5.85 mL,54.2 mmol) was added. The mixture was allowed to stir for 30 mins andconcentrated in vacuum to dryness. The residue was treated water (50mL), and extracted with ethyl acetate (2×50 mL). The organic layers werecombined dried over anhydrous MgSO₄, filtered, and excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography [(silica gel 25 g, eluting with ethylacetate/hexanes from 0 to 50%)] to furnish(3-Amino-4-fluorophenyl)(pyridin-2-yl)methanol (100b) (1.008 g, 85%yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (ddd, J=4.8,1.8, 0.9 Hz, 1H), 7.76 (td, J=7.7, 1.8 Hz, 1H), 7.50 (dt, J=8.0, 1.1 Hz,1H), 7.22 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 6.97-6.71 (m, 2H), 6.53 (ddd,J=8.3, 4.5, 2.1 Hz, 1H), 5.95 (d, J=4.0 Hz, 1H), 5.53 (d, J=4.0 Hz, 1H),5.07 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.67; MS(ES⁺): MS (ES+) 241.1 (M+Na), MS (ES+) 217.1 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100c)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.489 g, 5.3 mmol), (3-amino-4-fluorophenyl)(pyridin-2-yl)methanol(100c) (0.963 g, 4.41 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (2.469 g, 5.30 mmol) was addedN,N-dimethylformamide (DMF 27 mL) and N-ethyl-N-isopropylpropan-2-amine(DIPEA) (3.84 mL, 22.06 mmol) successively in a positive flow ofnitrogen at room temperature. The resulting reaction mixture was stirredat room temperature for 16 h under a positive flow of nitrogenatmosphere. Excess DMF was pumped-off under reduced pressure. Theresidue was treated with water (30 mL), and extracted with chloroform(2×50 mL). The combined organic layers were dried over anhydrous MgSO₄,filtered, evaporated to dryness. The residue was purified by flashcolumn chromatography [silica gel 40 g, eluting with methanol inchloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100c) (1.114 g, 52% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.54 (s, 1H, D₂O exchangeable), 8.45 (ddd, J=4.8, 1.9, 0.9 Hz, 1H),8.19-8.08 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.94-7.86 (m, 1H),7.83-7.68 (m, 3H), 7.55 (d, J=7.7 Hz, 2H), 7.35-7.17 (m, 3H), 6.22 (d,J=4.2 Hz, 1H, D₂O exchangeable), 5.69 (d, J=4.2 Hz, 1H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.98, −123.06; IR (KBr, cm⁻¹): 2236 cm⁻¹ (—CNstretching); MS (ES⁺): MS (ES+) 482.1 (M+1), MS (ES−) 480.25 (M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100d)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100c) (0.814 g, 1.691 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.370 mL, 5.07 mmol), warmed to room temperatureand stirred for 12 h. The reaction mixture was quenched withcyclopropylmethanamine (0.724 mL, 8.45 mmol) stirred for 1 h at roomtemperature, and concentrated in vacuum to dryness. The residue wasdissolved in cyclopropylmethanamine (2.90 mL, 33.8 mmol) andacetonitrile (20 mL) and the reaction mixture was heated at 100° C. for16 h TLC analysis (CHCl₃/MeOH, 9/1, v/v) shows reaction was complete,reaction mixture was evaporated to dryness. The residue was purified byflash column chromatography (silica gel 40 g, eluting 0-100% methanol inchloroform from 0-100%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100d) (696 mg, 77% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.54 (s, 1H, D₂O exchangeable), 8.55-8.41 (m, 1H), 8.18-8.08 (m, 1H),8.00 (dt, J=7.7, 1.4 Hz, 1H), 7.94-7.86 (m, 1H), 7.80-7.69 (m, 3H), 7.57(dd, J=7.5, 2.2 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.32 (ddd, J=8.5, 4.9,2.1 Hz, 1H), 7.27-7.14 (m, 2H), 4.93 (s, 1H), 3.01-2.68 (m, 1H, D₂Oexchangeable), 2.29 (qd, J=12.1, 6.6 Hz, 2H), 1.03-0.76 (m, 1H),0.48-0.30 (m, 2H), 0.03 (dt, J=7.6, 4.4 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.98, −123.05; IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CN stretching);MS (ES⁺): MS (ES+) 535.2 (M+1), MS (ES−) 533.2 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100e)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100d) (0.651 g, 1.218 mmol) in anhydrous methanol (30 mL) cooled to 0°C. was added nickel(II) chloride hexahydrate (0.434 g, 1.827 mmol)followed by sodium borohydride (0.369 g, 9.74 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 min, TLCanalysis (methanol/chloroform, 1/9, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (1.316 mL, 12.18 mmol)was added. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with saturated aqueous NH₄Cl (30 mL), andproduct was extracted with chloroform (2×30 mL). The combined organiclayers were dried over MgSO₄, filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [(silica gel 40 g,eluting with methanol/chloroform from 0 to 50%)] to furnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100e) (267 mg, 41% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.55 (s, 1H, D₂O exchangeable), 8.47 (dt, J=4.6, 1.5 Hz,1H), 7.74 (td, J=7.7, 1.8 Hz, 1H), 7.60 (d, J=9.2 Hz, 2H), 7.54 (s, 1H),7.49-7.40 (m, 3H), 7.39-7.26 (m, 2H), 7.26-7.16 (m, 2H), 4.91 (s, 1H),3.82 (s, 2H), 2.39-2.19 (m, 2H), 0.99-0.79 (m, 1H), 0.51-0.22 (m, 2H),0.04 (dd, J=5.4, 3.5 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.76,−123.48; MS (ES⁺): MS (ES+) 539.2 (M+1), MS (ES−) 573.2 (M+Cl), 537.2(M−1); Analysis calculated for: C₂₈H₂₆F₄N₆O.0.75H₂O: C, 60.92; H, 5.02;N, 15.22; Found: C, 60.84; H, 4.99; N, 14.93.

To a solution of free base of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(100e) (0.228 g, 0.423 mmol) in IPA (10 mL) was added conc. HCl (0.176mL, 2.117 mmol) and concentrated in vacuum to dryness. The residue wasdried in vacuum to remove excess HCl and dissolved in IPA (2 mL) withheating to solubilize. To the homogenous solution was added ether (40mL) and heated at reflux for 30 mins. After cooling to room temperaturethe solid obtained was collected by filtration, washed with ether anddried under vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.230 g, 84% yield) hydrochloride salt as a white solid; ¹H NMR (300MHz, Deuterium Oxide) δ 8.65 (d, J=4.9 Hz, 1H), 7.84 (t, J=7.4 Hz, 1H),7.77 (d, J=6.4 Hz, 1H), 7.67-7.56 (m, 4H), 7.50-7.29 (m, 5H), 5.71 (s,1H), 4.27 (s, 2H), 2.93 (d, J=7.4 Hz, 2H), 1.15-1.02 (m, 1H), 0.73-0.56(m, 2H), 0.37-0.17 (m, 2H); ¹⁹F NMR (282 MHz, D₂O) 6-62.36, −121.61; MS(ES+) 539.3 (M+1); (ES−) 537.2 (M−1); Analysis calculated forC₂₈H₂₆F₄N₆O.2.4HCl.2H₂O: C, 50.79; H, 4.93; Cl, 12.85; N, 12.69; Found:C, 50.79; H, 5.05; Cl, 12.82; N, 12.33.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101e) Step-1: Preparation of(4-Fluoro-3-nitrophenyl)(thiazol-2-yl)methanol (101a)

To a solution of 2-bromothiazole (4.8 mL, 52.2 mmol) in ether (36 mL) at−78° C. was added dropwise n-BuLi ((33.0 mL, 52.9 mmol) and stirred for30 mins at −78° C. To the 2-lithiated thiazole anion was added dropwisea solution of 4-fluoro-3-nitrobenzaldehyde (48a) (8.83 g, 52.2 mmol) inTHF (54 mL) at −78° C. and stirred at −78° C. for 2 h and at roomtemperature for 2 h. The reaction mixture was quenched with saturatedammonium chloride (80 mL). The organic layer was separated, dried,filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 120 g, eluting with0-100% ethyl acetate in hexane) to afford(4-fluoro-3-nitrophenyl)(thiazol-2-yl)methanol (101a) (3.5 g, 26%) as abrown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.27-8.19 (m, 1H), 7.89 (dddd,J=8.7, 4.4, 2.3, 0.6 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz,1H), 7.59 (dd, J=11.3, 8.6 Hz, 1H), 7.22 (d, J=4.9 Hz, 1H), 6.14 (dd,J=4.8, 0.9 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO) δ −120.63; MS (ES+) 277.0(M+Na), (ES−) 253.0 (M−1).

Step-2: Preparation of (3-Amino-4-fluorophenyl)(thiazol-2-yl)methanol(101b)

To a stirred solution of (4-fluoro-3-nitrophenyl)(thiazol-2-yl)methanol(101a) (2.8 g, 11.01 mmol) in anhydrous methanol (50 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (3.27 g, 13.77 mmol)followed by sodium borohydride (1.25 g, 33 mmol) portionwise over a 30mins period. The reaction mixture was stirred for 15 min at roomtemperature. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (3.57 mL, 33 mmol) stirred for 30minutes and concentrated in vacuum to dryness. The residue was dissolvedin ethyl acetate (50 mL) and water (50 mL). The organic layer wasseparated washed with brine (25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting with ethyl acetate/hexanes 0 to 100%)] tofurnish (3-amino-4-fluorophenyl)(thiazol-2-yl)methanol (101b) (1.234 g,5.50 mmol, 50.0% yield) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.68 (d, J=3.2 Hz, 1H), 7.61 (d, J=3.2 Hz, 1H), 6.91 (dd, J=11.5, 8.3Hz, 1H), 6.83 (dd, J=8.9, 2.2 Hz, 1H), 6.63 (d, J=4.1 Hz, 1H), 6.60-6.52(m, 1H), 5.77 (d, J=4.1 Hz, 1H), 5.14 (s, 2H); 19F NMR (282 MHz, DMSO) δ−136.87; MS(ES+) 247.1 (M+Na); (ES−) 223.0 (M−1).

Step-3: Preparation of1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.547 g, 5.50 mmol) in DMF (32.5 mL) was added(3-amino-4-fluorophenyl)(thiazol-2-yl)methanol (101b) (1.234 g, 5.50mmol), N-ethyl-N-isopropylpropan-2-amine (4.79 mL, 27.5 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 3.08 g,6.60 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h, quenched with water (100 mL) and extracted withethyl acetate (2×100 mL). The organic layers were combined washed withwater (2×50 mL), brine (50 mL), dried, filtered, and evaporated todryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-100%) to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101c) (1.01 g, 2.072 mmol, 37.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.13 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz,1H), 7.93-7.87 (m, 1H), 7.76-7.69 (m, 3H), 7.66-7.58 (m, 2H), 7.39-7.21(m, 2H), 6.92 (d, J=4.4 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H); MS(ES+) 488.1(M+1); 510.1 (M+Na).

Step-4: Preparation of1-(3-Cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101d)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101c) (0.75 g, 1.539 mmol) in dichloromethane (25 mL) at 0° C. wasadded thionyl chloride (0.337 mL, 4.62 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (0.4 mL, 4.62 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(10 mL) and added cyclopropylmethanamine (2.67 mL, 30.8 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (50 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%methanol in chloroform) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101d) (0.22 g, 0.407 mmol, 26.5% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.00 (dt,J=7.8, 1.3 Hz, 1H), 7.94-7.86 (m, 1H), 7.77-7.70 (m, 2H), 7.66 (d, J=3.2Hz, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.62-7.55 (m, 1H), 7.41-7.30 (m, 1H),7.26 (dd, J=10.3, 8.5 Hz, 1H), 5.19 (s, 1H), 2.98 (s, 1H), 2.37 (d,J=6.0 Hz, 3H), 0.98-0.82 (m, 1H), 0.43-0.34 (m, 2H), 0.11-0.02 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98, −122.16; MS (ES+) 541.2 (M+1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101e)

To a solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101d) (0.2 g, 0.370 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.110 g, 0.463 mmol) followed byportionwise addition of sodium borohydride (0.07 g, 1.85 mmol) over aperiod of 15 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.120 mL,1.110 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness and the residue obtainedwas dissolved in chloroform (25 mL) and water (25 mL). The aqueous layerwas separated extracted with chloroform (25 mL). The combined extractswere washed with brine (25 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting with 0-25%chloroform/methanol) to furnish1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(101e) (0.07 g, 0.129 mmol, 34.7% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.49 (s, 1H), 7.63-7.48 (m, 4H), 7.45 (s, 1H),7.42-7.23 (m, 5H), 7.25-7.12 (m, 1H), 5.11 (s, 1H), 3.73 (s, 2H), 2.94(s, 2H), 2.29 (dd, J=6.7, 2.3 Hz, 2H), 0.93-0.77 (m, 1H), 0.37-0.27 (m,2H), 0.04-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.75, −122.60; MS(ES+) 545.3 (M+1); (ES−) 543.2 (M−1); Analysis calculated forC₂₆H₂₄F₄N₆OS.0.25H₂O: C, 56.87; H, 4.50; N, 15.31; S, 5.84; Found: C,57.04; H, 4.74; N, 14.65; S, 4.86.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(53c) (0.6 g, 1.182 mmol) in dichloromethane (20 mL) at 0° C. was addedthionyl chloride (0.250 mL, 3.38 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was quenched with triethyl amine (1.450mL, 10.41 mmol) stirred at room temperature for 1 h, addedcyclopropylmethanamine (1.751 g, 23.89 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to remove dichloromethane. To the reaction mixture wasacetonitrile (10 mL) and added cyclopropylmethanamine (1.751 g, 23.89mmol). The reaction mixture was heated at reflux overnight, cooled toroom temperature and concentrated in vacuum to dryness. The residue wasdissolved in chloroform (120 mL), washed with water (60 mL), dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel 40 g, eluting withhexanes/ethyl acetate 1:0 to 2:1) to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102a) (132 mg, 20%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 8.31 (t, J=2.0 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.07 (ddd,J=8.2, 2.4, 1.0 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.3,2.2, 1.1 Hz, 1H), 7.88-7.83 (m, 1H), 7.78-7.66 (m, 3H), 7.60 (t, J=8.0Hz, 2H), 7.33-7.20 (m, 2H), 5.02 (s, 1H), 2.36-2.22 (m, 2H), 1.01-0.87(m, 1H), 0.45-0.32 (m, 2H), 0.09-0.02 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.97; MS (ES+) 561.3 (M+1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102b)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102a) (123 mg, 0.219 mmol) in MeOH (5 mL) cooled with ice/water wasadded nickel(II) chloride (66.0 mg, 0.278 mmol) followed by addition ofSodium borohydride (51.0 mg, 1.321 mmol) in portions over 5 min andstirred at room temperature for 1 h. The reaction mixture was treatedN1-(2-aminoethyl)ethane-1,2-diamine (0.08 mL, 0.733 mmol) stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (100 mL), washed with water (60mL). The aqueous phase was extracted again with ethyl acetate (60 mL).The combined extracts were washed with brine (60 mL), dried over MgSO₄followed by filtration and concentration. The crude product was purifiedby flash column chromatography [silica gel, eluting withchloroform/CMA80 (1:0 to 1:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(102b) (47 mg, 40%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.49-7.09 (m, 7H), 6.86 (t,J=7.7 Hz, 1H), 6.57-6.52 (m, 1H), 6.49 (d, J=7.8 Hz, 1H), 6.32 (dd,J=7.9, 2.2 Hz, 1H), 4.95 (s, 2H), 4.57 (s, 1H), 3.73 (s, 2H), 2.23 (d,J=6.7 Hz, 2H), 2.06 (bs, 2H), 0.95-0.77 (m, 1H), 0.40-0.25 (m, 2H),0.04-−0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71; MS (ES+):535.29 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103a)

To a solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (0.602 g, 1.325 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.290 mL, 3.97 mmol) and stirred at roomtemperature for 3 h. The reaction was evaporated to dryness and residuedissolved in N,N dimethyl formamide (20 mL). To the solution was added1H-pyrrole (3.68 mL, 53.0 mmol) and heated to reflux for 18 h.Additional 1H-pyrrole (3.68 mL, 53.0 mmol) was added and reaction heatedat reflux for 54 h. Excess solvent was pumped-off under reducedpressure. The residue was diluted with water (50 mL) and extracted withchloroform (2×50 mL). The combined organics were dried over anhydrousMgSO₄, filtered, evaporated to dryness. The residue was purified byflash column chromatography [silica gel 25 g, eluting with methanol inchloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103a) (0.063 g, 0.125 mmol, 9.45% yield) as a white waxy solid; MS(ES+) 504.34 (M+1), MS (ES−) 526.30 (M+Na), MS (ES−) 502.03 (M−1); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.94.

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103a) (55 mg, 0.109 mmol) in anhydrous methanol (10 mL) cooled to 0° C.was added nickel(II) chloride hexahydrate (0.039 g, 0.164 mmol) followedby sodium borohydride (0.033 g, 0.874 mmol) in small portions over aperiod of 5 min. The reaction mixture was stirred for 10 min, quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.118 mL, 1.092 mmol), stirredfor 30 mins and concentrated in vacuum to dryness. The reaction mixturewas treated with saturated aqueous NH₄Cl (30 mL), and product wasextracted with chloroform (2×30 mL). The combined organic layers weredried over MgSO₄, filtered and evaporated to dryness. The residue waspurified by flash column chromatography (silica gel 25 g, eluting withmethanol/chloroform from 0 to 100%) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(103b) (21 mg, 38% yield) as an off-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H, D₂O exchangeable), 10.53-10.42(m, 1H, D₂O exchangeable), 7.56 (s, 1H), 7.54-7.51 (m, 1H), 7.49-7.41(m, 4H), 7.32 (dt, J=6.2, 2.6 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.00 (dt,J=7.8, 1.3 Hz, 1H), 6.61 (q, J=2.4 Hz, 1H), 6.51 (q, J=2.0 Hz, 1H), 5.86(q, J=2.3 Hz, 1H), 3.78 (s, 2H), 3.72 (t, J=7.7 Hz, 1H), 2.09-1.80 (m,2H), 1.08 (tdd, J=16.9, 13.8, 7.2 Hz, 2H), 0.65 (ddt, J=10.1, 7.2, 3.7Hz, 1H), 0.45-0.25 (m, 2H), −0.02-−0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.71; MS (ES+) 508.3 (M+1), MS (ES−) 506.0 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104f) Step-1: Preparation of(3-aminophenyl)(1-methyl-1H-pyrazol-4-yl)methanol (104b)

To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (104a) (4.8 g, 43.6mmol) in tetrahydrofuran (80 mL) was cooled to 0° C. was added dropwise(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (49.0 mL,49.0 mmol) and stirred at 0° C. for 2 h. The reaction was quenched withsaturated aqueous NH₄Cl (120 mL) and extracted with ethyl acetate (2×120mL). The combined organic extracts were washed with brine (100 mL),dried over MgSO₄ followed by filtration and concentration. The residuewas dissolved in ether (200 mL), treated with 4 N HCl in 1,4-dioxane (24mL) and stirred at room temperature for 2 h. The solid obtained wascollected by filtration washed with ether, dried under vacuum to give(3-aminophenyl)(1-methyl-1H-pyrazol-4-yl)methanol (104b) (6.01 g, 68%)as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.47 (s, 1H),7.46-7.20 (m, 5H), 5.69 (s, 1H), 3.76 (s, 3H); MS (ES+) 204.1 (M+1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(4.15 g, 14.76 mmol) in DMF (80 mL) was added(3-aminophenyl)(1-methyl-1H-pyrazol-4-yl)methanol (104b) (2.99 g, 14.76mmol), N-ethyl-N-isopropylpropan-2-amine (21.00 mL, 121 mmol),bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP, 7.02g, 14.76 mmol) and stirred at room temperature for 13 h. The reactionmixture was diluted with ethyl acetate (300 mL), washed with water(2×120 mL) brine (120 mL), dried over MgSO₄, filtered and concentratedin vacuum to dryness. The crude product was purified by flash columnchromatography [silica gel 120 g, eluting with hexanes/ethyl acetate(1:0 to 0:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104c) (2.9 g, 42%) as a light brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H),7.95 (s, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73 (t, J=0.9 Hz,1H), 7.63 (t, J=1.9 Hz, 1H), 7.59-7.54 (m, 1H), 7.41 (s, 1H), 7.28 (t,J=7.8 Hz, 1H), 7.21 (d, J=0.8 Hz, 1H), 7.16-7.10 (m, 1H), 5.67 (d, J=4.3Hz, 1H), 5.61 (d, J=4.4 Hz, 1H), 3.75 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.97; MS (ES+) 467.2 (M+1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104c) (2.836 g, 6.08 mmol) in dichloromethane (100 mL) at 0° C. wasadded thionyl chloride (1.100 mL, 14.87 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was treated with triethylamine (7.00 mL, 50.2 mmol) and stirred at room temperature for 1 h. Itwas then treated with cyclopropylmethanamine (8.00 g, 109 mmol) andconcentrated to remove most of dichloromethane followed by addition ofacetonitrile (75 mL). The reaction mixture was stirred at 70° C. for 20h and concentrated to dryness. The residue was treated with chloroform(240 mL), washed with water (100 mL), dried over MgSO₄ followed byfiltration and concentration. The crude product was purified by flashcolumn chromatography [silica gel 40 g, eluting with chloroform/methanol(1:0 to 19:1)] to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104d) (1.518 g, 48%) as a brown solid, ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H),7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.69 (m, 2H), 7.63 (s, 1H),7.58-7.52 (m, 1H), 7.46 (s, 1H), 7.32-7.22 (m, 2H), 7.16 (d, J=7.8 Hz,1H), 4.74 (s, 1H), 3.74 (s, 3H), 2.35-2.15 (m, 2H), 0.96-0.78 (d, J=9.7Hz, 1H), 0.43-0.27 (m, 2H), 0.09-−0.020-0.00 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.96; MS (ES+) 520.3 (M+1).

Step-4: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(104e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104d) (1.453 g, 2.8 mmol) in MeOH (40 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.850 g, 8.39 mmol), nickel(II)chloride hexahydrate (0.360 g, 1.513 mmol) followed by addition ofSodium borohydride (1.083 g, 28.1 mmol) slowly over 5 min and stirred atroom temperature for 1 h. The reaction mixture quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.400 mL, 12.83 mmol), stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (200 mL) and washed with water(100 mL). The aqueous phase was extracted again with ethyl acetate (100mL). The combined organic extracts were washed with brine (100 mL),dried over MgSO₄ followed by filtration and concentration. The crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/methanol (1:0 to 19:1) to give tert-butyl3-(5-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(104e) (709 mg, 41%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69(s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.56-7.22 (m, 9H), 7.16 (d, J=7.7Hz, 1H), 4.73 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.74 (s, 3H), 2.27 (t,J=6.4 Hz, 2H), 1.37 (s, 9H), 0.96-0.79 (m, 1H), 0.48-0.27 (m, 2H),0.09-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80; MS (ES+) 624.4(M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104f)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(104e) (0.614 g, 0.984 mmol) in 1,4-Dioxane (60 mL) was added hydrogenchloride (10.0 mL, 40.0 mmol, 4 M in 1,4-dioxane) stirred at roomtemperature for 15.5 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 1:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(104f) (363 mg, 70%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 7.61 (t, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.57-7.45 (m, 2H),7.48-7.39 (m, 3H), 7.37-7.30 (m, 1H), 7.29-7.22 (m, 2H), 7.19-7.12 (m,1H), 4.72 (s, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 2.36-2.18 (m, 3H),0.97-0.79 (m, 1H), 0.43-0.30 (m, 2H), 0.10-0.01 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.72; MS (ES+) 525.3 (M+1); (ES−) 522.323 (M−1); IR(KBr pellet, cm⁻¹): 3429, 2925, 1616, 1559, 1243; Analysis calculatedfor C₂₇H₂₈F₃N₇O.0.25CHCl₃: C, 59.14; H, 5.15; N, 17.72; Found: C, 59.07;H, 5.24; N, 17.57.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105g) Step-1: Preparation of (4-methoxyphenyl)(3-nitrophenyl)methanone(105c)

To a stirred solution of 3-nitro-benzoic acid (105a) (5.0 g, 29.92 mmol)in toluene (150 mL) at room temperature was added DMF (5 drops) andSOCl₂ (10.67 g, 89.76 mmol). The reaction mixture was heated at 70° C.for 3 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in DCM (100 mL), methoxybenzene (105b) (8.2 mL, 76.1 mmol) wasadded at room temperature and the reaction mixture was heated to 50° C.AlCl₃ (15.95 g, 119.672 mmol) was added portion wise to the hot reactionmixture and stirred at 50° C. for 30 min. Completion of the reaction wasmonitored by TLC (20% EtOAc in n-Hexane), two spots were observed inTLC. Reaction mixture was cooled to room temperature and was poured intocrushed Ice. Conc. HCl (6 mL) was added to the mixture and extractedwith EtOAc (2×100 mL). The organic layers were combined washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuum.The residue obtained was purified by flash chromatography (silica gel,eluting with 0-40% EtOAc in hexane) to afford(4-Methoxy-phenyl)-(3-nitro-phenyl)methanone (105c) (3.6 g, 46%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (ddd, J=8.2, 2.4, 1.1Hz, 1H), 8.40 (t, J=1.9 Hz, 1H), 8.15-8.09 (m, 1H), 7.86 (d, J=8.0 Hz,1H), 7.84-7.76 (m, 2H), 7.17-7.09 (m, 2H), 3.88 (s, 3H).

Step-2: Preparation of (3-aminophenyl)(4-methoxyphenyl)methanol (105d)

To a stirred solution of (4-methoxyphenyl)-(3-nitrophenyl)methanone(105c) (3.5 g, 13.61 mmol) in methanol (135 mL) was added NiCl₂.6H₂O(0.646 g, 2.72 mmol) at room temperature. Reaction mixture was cooled to0° C. and NaBH₄ was added portion wise at this temperature. Reactionmixture was warmed to room temperature and continued stirring for 3 h.Completion of reaction was monitored by TLC (35% EtOAc in n-Hexane). Thereaction mixture was quenched with N1-(2-aminoethyl)ethane-1,2-diamine(2.5 mL), stirred for 30 min and concentrated in vacuum to dryness. Theresidue obtained was dissolved in (1:1) ethyl acetate/water (100 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (50 mL). The organic layers were combined, dried, filteredand concentrated in vacuum to dryness. The residue obtained was purifiedby flash chromatography (silica gel, eluting with EtOAc in hexane 0 to30%) to afford (3-aminophenyl)-(4-methoxyphenyl)methanol (105d) (1.6 g,51%) as a light brown oily syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 7.30-7.22(m, 2H), 6.94 (t, J=7.7 Hz, 1H), 6.90-6.83 (m, 2H), 6.59 (t, J=1.9 Hz,1H), 6.52 (dt, J=7.6, 1.3 Hz, 1H), 6.41 (ddd, J=7.9, 2.3, 1.0 Hz, 1H),5.60 (d, J=3.9 Hz, 1H), 5.49 (d, J=3.9 Hz, 1H), 5.00 (s, 2H), 3.74 (s,3H).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105e)

To a solution of2-(3-Cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (9i)(2.24 g, 7.82 mmol) in toluene (50 mL) was added DMF (5 drops), SOCl₂(1.36 mL, 18.77 mmol) at 0° C. Reaction mixture was heated at reflux for3.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (50 mL) and added(3-aminophenyl)-(4-methoxyphenyl)methanol (105d) (1.5 g, 6.54 mmol)followed by drop wise addition of triethylamine (8.8 mL) at roomtemperature. The reaction mixture was stirred at room temperatureovernight. Reaction mixture was concentrated in vacuum to dryness andthe residue obtained was purified by flash chromatography (silica gel,eluting with ethyl acetate in hexane 10-50%) to afford1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105e) (2.6 g,81%) as a light brown syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 10.62 (s, 1H),8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.4 Hz, 1H), 7.90 (ddd, J=8.2,2.2, 1.1 Hz, 1H), 7.77-7.69 (m, 2H), 7.61 (t, J=1.8 Hz, 1H), 7.54 (d,J=8.3 Hz, 1H), 7.31-7.18 (m, 3H), 7.11 (d, J=7.7 Hz, 1H), 6.92-6.80 (m,2H), 5.84 (d, J=3.9 Hz, 1H), 5.62 (d, J=3.9 Hz, 1H), 3.71 (s, 3H).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105f)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105e) (2.6 g, 5.28 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (1.2 g, 10.15 mmol) and allowed to warm to roomtemperature over 3 h. The reaction mixture was quenched withcyclopropylmethanamine (8 mL), stirred for 1 h at room temperature andheated at 50° C. for 17 h. The reaction mixture was concentrated invacuum to dryness dissolved in chloroform (50 mL), washed with water (25mL), dried, filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, eluting0-50% ethyl acetate/methanol 9:1 in hexane) to afford1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105f) (1.7 g, 59%) as a light brown semisolid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.59 (s, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.95 (dt, J=7.8, 1.3Hz, 1H), 7.85 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73-7.64 (m, 2H), 7.60 (t,J=1.8 Hz, 1H), 7.54-7.46 (m, 1H), 7.29-7.09 (m, 4H), 6.85-6.75 (m, 2H),4.73 (s, 1H), 3.65 (s, 3H), 2.23 (d, J=6.7 Hz, 2H), 0.94-0.79 (m, 1H),0.38-0.25 (m, 2H), 0.05-−0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.97;IR (KBr) 2234 cm⁻¹; MS (ES+) 546.3 (M+1); (ES−) 545.4 (M−1); Analysiscalculated for C₃₀H₂₆F₃N₅O₂.0.5CH₂Cl₂: C, 62.30; H, 4.63; N, 11.91;Found: C, 62.73; H, 4.74; N, 11.60.

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105f) (0.5 g, 0.916 mmol) in anhydrous methanol (20 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (0.272 g, 1.146 mmol),sodium borohydride (0.173 g, 4.58 mmol) was added to the reactionmixture in small portions over a 15 min period. The reaction mixture wasstirred for 15 min at 0° C. and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.297 mL, 2.75 mmol) stirred for 30mins and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (25 mL) and water (25 mL). The organiclayer was separated, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% methanol in chloroform) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(105g) (0.35 g, 0.637 mmol, 69.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.78 (s, 1H), 7.72 (t, J=1.7 Hz, 1H), 7.67 (s, 2H),7.61 (dt, J=7.3, 1.7 Hz, 1H), 7.58-7.47 (m, 3H), 7.37-7.29 (m, 2H), 7.26(d, J=7.3 Hz, 2H), 6.90-6.83 (m, 2H), 4.88 (s, 1H), 4.12 (s, 2H), 3.70(s, 3H), 2.34 (d, J=6.8 Hz, 2H), 1.03-0.87 (m, 1H), 0.45-0.35 (m, 2H),0.07 (dd, J=5.5, 3.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+)550.4 (M+1); (ES−) 548.3 (M−1); Analysis Calculated forC₃₀H₃₀F₃N₅O₂.1.1HCl.H₂O: C, 59.29; H, 5.49; Cl, 6.42; N, 11.52; Found:C, 59.08; H, 5.43; Cl, 6.19; N, 11.17.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(106a)

To a solution of tert-butyl3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(49g) (0.111 g, 0.153 mmol) in methanol (10 mL) was added hydrogenchloride (4N in dioxane, 1.912 mL, 7.65 mmol) stirred for 14 h at roomtemperature. Excess solvent was pumped-off under reduced pressure. Theresidue was purified by flash column chromatography (first column:silica gel 25 g, eluting with CMA80 in chloroform, second column: silicagel 25 g, then 0-100% methanol in chloroform from 0-100%) to afford1-(3-(aminomethyl)phenyl)-N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(106a) (22 mg, 23% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.66 (s, 1H, D₂O exchangeable), 7.67-7.62 (m, 1H), 7.58-7.49 (m, 3H),7.47-7.28 (m, 9H), 7.24-7.13 (m, 2H), 7.08 (d, J=7.7 Hz, 1H), 7.01 (d,J=8.1 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 5.20 (s, 1H), 5.09 (s, 2H), 3.76(s, 2H), 2.31 (dd, J=12.0, 6.7 Hz, 1H), 2.21 (dd, J=11.9, 7.0 Hz, 1H),0.87 (p, J=6.5 Hz, 1H), 0.45-0.23 (m, 2H), −0.01 (s, 2H); ¹H NMR (300MHz, DMSO-d₆, D₂O) δ 7.68-7.63 (m, 1H), 7.54-7.49 (m, 3H), 7.49-7.40 (m,4H), 7.33 (tt, J=5.1, 2.2 Hz, 5H), 7.26-7.14 (m, 2H), 7.10 (d, J=7.7 Hz,1H), 7.02 (d, J=8.1 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 5.20 (s, 1H), 5.08(s, 2H), 3.74 (s, 2H), 2.37-2.15 (m, 2H), 0.85 (h, J=6.6 Hz, 1H),0.44-0.28 (m, 2H), −0.01-−0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.71; MS (ES⁺): MS (ES+) 626.4 (M+1), MS (ES−) 624.3 (M−1).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107f)Step-1: Preparation of (3-Aminophenyl)(3-(benzyloxy)phenyl)methanol(107b)

To a stirred solution of 3-(benzyloxy) benzaldehyde (107a) (2.122 g, 10mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (3.55 g,12.00 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%) to furnish(3-Aminophenyl)(3-(benzyloxy)phenyl)methanol (107b) (1.258 g, 41% yield)as a thick yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.47-7.29 (m, 5H),7.19 (t, J=7.9 Hz, 1H), 7.05-6.97 (m, 1H), 6.96-6.86 (m, 2H), 6.83 (ddd,J=8.2, 2.7, 1.0 Hz, 1H), 6.58 (t, J=1.9 Hz, 1H), 6.50 (dt, J=7.6, 1.3Hz, 1H), 6.38 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.69 (d, J=3.9 Hz, 1H, D₂Oexchangeable), 5.46 (d, J=3.9 Hz, 1H), 5.05 (s, 2H), 4.98 (s, 2H, D₂Oexchangeable); MS (ES⁺): MS (ES+) 328.2 (M+Cl), MS (ES−) 304.2 (M−1).

Step-2: Preparation ofN-(3-((3-(Benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.215 g, 4.32 mmol) in DMF (10 mL) was added(3-aminophenyl)(3-(benzyloxy)phenyl)methanol (107b) (1.2 g, 3.93 mmol),N-ethyl-N-isopropylpropan-2-amine (3.42 mL, 19.65 mmol), andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 2.198 g,4.72 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (25 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and evaporated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexanes) to furnishN-(3-((3-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107c) (1.637 g, 2.88 mmol, 73.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.16 (td, J=1.7, 0.9 Hz, 1H), 8.03-7.95(m, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.77-7.68 (m, 2H), 7.64 (t,J=1.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.46-7.30 (m, 5H), 7.23 (dt, J=15.5,7.9 Hz, 2H), 7.17-7.10 (m, 1H), 7.02 (dd, J=2.6, 1.5 Hz, 1H), 6.95-6.89(m, 1H), 6.85 (ddd, J=8.1, 2.7, 1.0 Hz, 1H), 5.95 (d, J=3.8 Hz, 1H),5.63 (d, J=3.9 Hz, 1H), 5.05 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.97;MS (ES−) 567.3 (M−1).

Step-3: Preparation ofN-(3-((3-(Benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107d)

To a solution ofN-(3-((3-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107c) (1.637 g, 2.88 mmol) in dichloromethane (50 mL) at 0° C. wasadded thionyl chloride (0.63 mL, 8.64 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (0.749 mL, 8.64 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(10 mL) and added cyclopropylmethanamine (4.99 mL, 57.6 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (50 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-100%ethyl acetate in hexane) to affordN-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107d) (1.16 g, 1.866 mmol, 64.8% yield) as a yellow solid; ¹HNMR (300MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.8,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75-7.66 (m, 3H), 7.55(dt, J=7.9, 1.5 Hz, 1H), 7.45-7.40 (m, 3H), 7.39-7.37 (m, 1H), 7.36-7.31(m, 2H), 7.25-7.16 (m, 3H), 7.09-7.06 (m, 1H), 6.97 (d, J=7.6 Hz, 1H),6.83 (ddd, J=8.2, 2.6, 1.0 Hz, 1H), 5.04 (s, 2H), 4.79 (s, 1H), 2.35 (s,1H), 2.27 (s, 2H), 1.01-0.84 (m, 1H), 0.42-0.32 (m, 2H), 0.05 (dd,J=5.2, 3.8 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.95; MS (ES+) 622.4(M+1); (ES−) 620.3 (M−1).

Step-4: Preparation of tert-Butyl3-(5-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(107e)

To a solution ofN-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107d) (1.0 g, 1.609 mmol) in MeOH (10 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.053 g, 4.83 mmol) and nickel(II)chloride (0.421 g, 1.769 mmol). sodium borohydride (0.497 g, 12.87 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.527 mL, 4.83 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(107e) (0.304 g, 0.419 mmol, 26.0% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.58(s, 1H), 7.51 (q, J=7.1, 6.3 Hz, 2H), 7.46-7.30 (m, 9H), 7.27-7.14 (m,3H), 7.11-7.05 (m, 1H), 6.97 (d, J=7.7 Hz, 1H), 6.83 (ddd, J=8.2, 2.6,1.0 Hz, 1H), 5.05 (s, 2H), 4.78 (s, 1H), 4.18 (d, J=6.2 Hz, 2H), 2.35(s, 1H), 2.27 (s, 2H), 1.36 (s, 9H), 0.92 (dd, J=13.2, 6.3 Hz, 1H),0.42-0.31 (m, 2H), 0.04 (q, J=5.8, 5.3 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.80; MS (ES+) 726.5 (M+1); (ES−) 724.5 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107f)

To a solution of tert-butyl3-(5-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(107e) (0.125 g, 0.172 mmol) in methanol (Volume: 7.5 mL) was addedhydrogen chloride (0.359 mL, 4.31 mmol), stirred at room temperatureovernight and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 12 g, elutingwith 0-50% methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107f) (0.05 g, 0.080 mmol, 46.4% yield) as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.84 (s, 1H), 8.50 (d, J=59.1 Hz, 2H), 7.76 (s,1H), 7.72 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.64-7.49 (m, 4H), 7.46-7.21(m, 9H), 7.06 (d, J=7.4 Hz, 1H), 6.90 (dd, J=8.0, 2.5 Hz, 1H), 5.08 (s,3H), 4.11 (s, 2H), 2.47-2.38 (m, 2H), 1.09-0.93 (m, 1H), 0.44 (td,J=5.3, 4.8, 2.8 Hz, 2H), 0.25-0.07 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.78; MS (ES+) 626.4 (M+1); (ES−) 624.4 (M−1); Analysis calculated forC₃₆H₃₄F₃N₅O₂.1.5HCl.H₂O: C, 61.91; H, 5.41; Cl, 7.61; N, 10.03: Found:C, 61.51; H, 5.51; Cl, 7.89; N, 9.85.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108e)Step-1: Preparation of 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile(108a)

To a stirred solution of 3-formylbenzonitrile (54a) (1.311 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (108a)(0.652 g, 29% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.76(t, J=1.7 Hz, 1H), 7.73-7.63 (m, 2H), 7.51 (t, J=7.7 Hz, 1H), 6.94 (t,J=7.7 Hz, 1H), 6.60-6.48 (m, 2H), 6.40 (ddd, J=7.9, 2.3, 1.1 Hz, 1H),5.97 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.58 (d, J=3.9 Hz, 1H), 5.04(s, 2H, D₂O exchangeable); MS (ES⁺): MS (ES+) 225.2 (M+1), 247.1 (M+Na),223.1 (M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.897 g, 3.19 mmol) in DMF (10 mL) was added3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (108a) (0.65 g, 2.90mmol), N-ethyl-N-isopropylpropan-2-amine (2.52 mL, 14.5 mmol) andbromo-tri s-pyrrolidino phosphoniumhexafluorophosphate(PyBrop) (1.62 g,3.48 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (25 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, elutingwith 0-100% ethyl acetate in hexanes) to furnish1-(3-Cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108b) (1.057 g, 2.169 mmol, 74.8% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H),7.77-7.62 (m, 5H), 7.61-7.56 (m, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.29 (t,J=7.8 Hz, 1H), 7.22-7.10 (m, 1H), 6.22 (d, J=3.9 Hz, 1H), 5.77 (d, J=4.0Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.96; MS (ES+) 510.2 (M+Na);(ES−) 486.2 (M−1); 973.3 (2M-1).

Step-3: Preparation of1-(3-Cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108c)

To a solution of1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108b) (1.057 g, 2.169 mmol) in dichloromethane (50 mL) at 0° C. wasadded thionyl chloride (0.48 mL, 6.51 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (0.564 mL, 6.51 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile (5mL) and added cyclopropylmethanamine (3.76 mL, 43.4 mmol). The reactionmixture was heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (50 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-100% ethyl acetate inhexane) to afford1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108c) (0.459 g, 0.849 mmol, 39.2% yield) as a yellow oil; ¹H NMR (300MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8,1.3 Hz, 1H), 7.94-7.86 (m, 2H), 7.77-7.64 (m, 5H), 7.60-7.46 (m, 2H),7.32-7.19 (m, 2H), 4.92 (s, 1H), 2.63 (s, 1H), 2.27 (s, 2H), 0.96-0.87(m, 1H), 0.44-0.39 (m, 2H), 0.08-0.02 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.96; MS (ES+) 541.304 (M+1); (ES−) 539.269 (M−1).

Step-4: Preparation of1-(3-(tert-Butoxycarbonylaminomethyl)phenyl)-N-(3-((3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108d)

To a solution of1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108c) (0.425 g,0.786 mmol) in MeOH (10 mL) cooled with ice/water was addeddi-tert-butyl dicarbonate (0.867 g, 3.93 mmol) and nickel(II) chloride(0.206 g, 0.865 mmol). Sodium borohydride (0.364 g, 9.44 mmol) was addedslowly over 15 min and reaction mixture was stirred at room temperaturefor 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.429 mL, 3.93 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford1-(3-(tert-butoxycarbonylaminomethyl)phenyl)-N-(3-((3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108d) (0.143 g, 0.191 mmol, 24.29%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.64(s, 1H), 7.57 (s, 1H), 7.55-7.32 (m, 7H), 7.31-7.14 (m, 5H), 7.04 (d,J=7.0 Hz, 1H), 4.78 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 4.07 (d, J=6.2 Hz,2H), 2.38-2.19 (m, 3H), 1.37 (d, J=3.2 Hz, 18H), 0.98-0.82 (m, 1H),0.44-0.31 (m, 2H), 0.11-0.01 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ−60.81; MS (ES+) 749.5 (M+1); (ES−) 747.5 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108e)

To a solution of1-(3-(tert-Butoxycarbonylaminomethyl)phenyl)-N-(3-((3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(108d) (0.148 g, 0.198 mmol) in methanol (10 mL) was added conc.hydrogen chloride (0.824 mL, 9.88 mmol), stirred at room temperatureovernight and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 12 g, elutingwith 0-100% CMA-80 in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108e)(0.05 g, 0.091 mmol, 46.1% yield) as an light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.67 (s, 1H), 7.66 (s, 1H), 7.60-7.11 (m, 12H), 4.79(s, 1H), 3.77 (s, 2H), 3.67 (s, 2H), 2.28 (d, J=6.7 Hz, 2H), 1.05-0.83(m, 1H), 0.51-0.30 (m, 2H), 0.05 (t, J=4.7 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO) δ −60.51; MS (ES+) 549.4 (M+1); (ES−) 547.4 (M−1); Analysiscalculated for C₃₀H₃₁F₃N₆O₂.0.5H₂O: C, 64.62; H, 5.78; N, 15.07; Found:C, 64.34; H, 5.73; N, 14.72.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109f) Step-1: Preparation of (3-aminophenyl)(3-methoxyphenyl)methanol(109b)

To a stirred solution of 3-methoxybenzaldehyde (109a) (1.361 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (12.50 mL, 25.00 mmol),stirred for 6 h. The reaction mixture was treated with 2 N NaOH (15.00mL, 30.0 mmol) and extracted with ethyl acetate (2×50 mL). The organiclayers were combined washed with sat. NH₄Cl (50 mL), dried overanhydrous MgSO₄, filtered, evaporated to dryness. The crude residue waspurified by flash column chromatography (silica gel 40 g, eluting with0-20% ethyl acetate in hexane) to furnish(3-aminophenyl)(3-methoxyphenyl)methanol (109b) (1.327 g, 58% yield) asa yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.18 (t, J=7.8 Hz, 1H),7.00-6.85 (m, 3H), 6.75 (ddd, J=8.2, 2.6, 1.0 Hz, 1H), 6.60-6.46 (m,2H), 6.37 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.68 (d, J=3.9 Hz, 1H, D₂Oexchangeable), 5.46 (d, J=3.9 Hz, 1H), 4.98 (s, 2H, D₂O exchangeable),3.71 (s, 3H); MS (ES⁺): MS (ES+) 230.2 (M+1), 252.1 (M+Na), 228.12(M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.754 g, 6.24 mmol) in DMF (10 mL) was added(3-aminophenyl)(3-methoxyphenyl)methanol (109b) (1.3 g, 5.67 mmol),N-ethyl-N-isopropylpropan-2-amine (4.94 mL, 28.4 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 3.17 g,6.80 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (25 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and evaporated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109c) (2.27 g, 4.61 mmol, 81% yield) as a yellow semisolid; ¹H NMR (300MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.21-8.12 (m, 1H), 8.00 (dt, J=7.8, 1.3Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.2 Hz, 1H), 7.79-7.68 (m, 2H),7.67-7.60 (m, 1H), 7.59-7.48 (m, 1H), 7.31-7.10 (m, 3H), 6.94 (t, J=2.0Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.77 (ddd, J=8.2, 2.7, 1.0 Hz, 1H),5.95 (d, J=3.8 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 3.71 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.96; MS (ES−) 491.2 (M−1).

Step-3: Preparation of1-(3-Cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109c) (2.27 g, 4.61 mmol) in dichloromethane (25 mL) at 0° C. was addedthionyl chloride (1 mL, 13.83 mmol) and stirred at room temperature for2 h. The reaction mixture was quenched with cyclopropylmethanamine(1.199 mL, 13.83 mmol) and stirred at room temperature for additional 5h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (10 mL) and addedcyclopropylmethanamine (8.00 mL, 92 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109d) (1.3 g, 2.383 mmol, 51.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.19-8.14 (m, 1H), 8.00 (dt, J=7.9, 1.3Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.69 (m, 2H), 7.67 (t,J=1.9 Hz, 1H), 7.54 (dt, J=8.0, 1.7 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H),7.23-7.19 (m, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.99 (dd, J=2.6, 1.5 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 6.75 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 4.79 (s,1H), 3.70 (s, 3H), 2.34 (s, 1H), 2.29 (d, J=7.1 Hz, 2H), 0.99-0.85 (m,1H), 0.43-0.33 (m, 2H), 0.09-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.95; IR (KBr) 2234 cm-1; MS (ES+) 546.3 (M+1); (ES−) 544.4 (M−1).

Step-4: Preparation of tert-Butyl3-(5-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(109e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109d) (1.2 g, 2.200 mmol) in MeOH (20 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.44 g, 6.6 mmol) and nickel(II)chloride (0.575 g, 2.420 mmol). Sodium borohydride (0.679 g, 17.60 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.720 mL, 6.60 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(109e) (0.375 g, 0.577 mmol, 26.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.67-7.62 (m, 1H), 7.58 (s, 1H), 7.52 (t,J=6.6 Hz, 1H), 7.49-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.28-7.13 (m, 3H),7.02-6.98 (m, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.75 (ddd, J=8.3, 2.6, 1.0Hz, 1H), 4.78 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 2.42-2.31(m, 1H), 2.29 (d, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.00-0.78 (m, 1H),0.45-0.29 (m, 2H), 0.12-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.79; MS (ES+) 650.4 (M+1); (ES−) 648.3 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109f)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(109e) (0.364 g, 0.560 mmol) in methanol (30 mL) was added conc.hydrogen chloride (1.167 mL, 14.01 mmol), stirred at room temperatureovernight and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 12 g, elutingwith 0-50% methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(109f) (0.160 g, 0.291 mmol, 52.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.76-7.68 (m, 3H), 7.65 (dt, J=7.4, 1.6Hz, 1H), 7.61-7.46 (m, 3H), 7.30-7.15 (m, 3H), 7.05-7.00 (m, 1H), 6.97(d, J=7.7 Hz, 1H), 6.81-6.71 (m, 1H), 4.83 (s, 1H), 4.09 (s, 2H), 3.71(s, 3H), 2.31 (dd, J=6.7, 2.5 Hz, 2H), 1.05-0.79 (m, 1H), 0.51-0.26 (m,2H), 0.16-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.59; MS (ES+)550.4 (M+1); (ES−) 548.3 (M−1); Analysis calculated forC₃₀H₃₀F₃N₅O₂.HCl.1.25H₂O: C, 59.21; H, 5.55; Cl, 5.83; N, 11.51; Found:C, 59.44; H, 5.64; Cl, 5.64; N, 11.15.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110f) Step-1: Preparation of (3-aminophenyl)(m-tolyl)methanol (110b)

To a stirred solution of 3-methylbenzaldehyde (110a) (1.179 mL, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (12.50 mL, 25 mmol), stirredfor 6 h. The reaction mixture was treated with 2 N NaOH (15 mL) andextracted with ethyl acetate (2×50 mL). The organic layers were combinedwashed with sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with ethyl acetate in hexanefrom 0-100%) to furnish (3-aminophenyl)(m-tolyl)methanol (110b) (1.393g, 65% yield) a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.22-7.09 (m,3H), 6.99 (dt, J=6.4, 1.9 Hz, 1H), 6.91 (t, J=7.7 Hz, 1H), 6.56 (t,J=2.0 Hz, 1H), 6.50 (dt, J=7.6, 1.3 Hz, 1H), 6.37 (ddd, J=7.9, 2.4, 1.1Hz, 1H), 5.64 (d, J=3.8 Hz, 1H, D₂O exchangeable), 5.45 (d, J=3.8 Hz,1H), 4.98 (s, 2H, D₂O exchangeable), 2.26 (s, 3H); MS (ES⁺) 214.2 (M+1),236.2 (M+Na), MS (ES−) 212.1 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110c)

In a 100 mL single-necked flask1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.74 (36.0 mL, 465 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA)(5.40 mL, 31.0 mmol) successively in a positive flow of nitrogen at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere.Excess DMF was pumped-off under reduced pressure. The residue wastreated with water (50 mL), and extracted with chloroform (2×50 mL)combined organics were dried over anhydrous MgSO₄, filtered, evaporatedto dryness. The residue was then purified by flash column chromatography[silica gel 40 g, eluting with methanol in chloroform from 0-100%] tofurnish1-(3-cyanophenyl)-N-(3-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110c) (2.308 g, 78% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.63 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.69 (m,2H), 7.62 (t, J=1.8 Hz, 1H), 7.55 (dd, J=8.1, 1.5 Hz, 1H), 7.26 (t,J=7.8 Hz, 1H), 7.22-7.10 (m, 4H), 7.01 (d, J=7.1 Hz, 1H), 5.90 (d, J=3.8Hz, 1H, D₂O exchangeable), 5.62 (d, J=3.8 Hz, 1H), 2.26 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.95; MS (ES⁺): MS (ES+) 499.2 (M+Na), 975.4(2M+Na), MS (ES−) 475.3 (M−1); IR (KBr, cm⁻¹): 2235 cm⁻¹ (—CNstretching).

Step-3: Preparation of1-(3-Cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110c) (2.31 g, 4.85 mmol) in dichloromethane (25 mL) at 0° C. was addedthionyl chloride (1.06 mL, 14.55 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was quenched with cyclopropylmethanamine(1.262 mL, 14.55 mmol) and stirred at room temperature for additional 5h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (10 mL) and addedcyclopropylmethanamine (8.41 mL, 97 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110d) (1.784 g, 3.37 mmol, 69.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.19-8.13 (m, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.79-7.69 (m, 2H),7.68-7.63 (m, 1H), 7.54 (dt, J=8.0, 1.7 Hz, 1H), 7.30-7.12 (m, 5H), 6.99(dd, J=6.3, 2.1 Hz, 1H), 4.77 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H),1.03-0.84 (m, 1H), 0.44-0.31 (m, 2H), 0.09-0.01 (m, 2H); ¹⁹F NMR (282MHz, DMSO) δ −60.94; IR (KBr) 2234 cm⁻¹; MS (ES+) 530.3 (M+1); (ES−)528.3 (M−1).

Step-4: Preparation of tert-Butyl3-(5-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(110e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110d) (1.2 g, 2.266 mmol) in MeOH (20 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.5 g, 6.87 mmol) and nickel(II)chloride (0.599 g, 2.52 mmol). Sodium Borohydride (0.708 g, 18.33 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.750 mL, 6.87 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase separated and extracted again with dichloromethane (60 mL). Theorganic extracts were combined, washed with brine (60 mL), dried overMgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (110e)(1.0 g, 1.578 mmol, 68.9% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.69 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (s, 1H),7.56-7.46 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.25 (d, J=7.7Hz, 1H), 7.22-7.13 (m, 4H), 6.99 (dt, J=6.7, 2.0 Hz, 1H), 4.76 (s, 1H),4.19 (d, J=6.2 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.36 (d, J=1.9 Hz,9H), 0.99-0.82 (m, 1H), 0.42-0.33 (m, 2H), 0.10-−0.01 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.80; MS (ES+) 634.4 (M+1); (ES−) 632.4 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110f)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(110e) (0.92 g, 1.452 mmol) in methanol (50 mL) was added conc. hydrogenchloride (3.02 mL, 36.3 mmol), stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 24 g, eluting with 0-50%methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(110f) (0.67 g, 1.256 mmol, 86% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.92 (s, 1H), 8.51 (t, J=55.0 Hz, 3H), 7.83 (s, 1H),7.72 (d, J=1.9 Hz, 1H), 7.71 (s, 1H), 7.64 (dt, J=7.2, 1.8 Hz, 1H),7.61-7.56 (m, 1H), 7.56-7.48 (m, 2H), 7.47-7.34 (m, 3H), 7.28 (t, J=7.9Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 5.36 (s, 1H), 4.12 (s, 2H), 2.70-2.57(m, 2H), 2.29 (s, 3H), 1.20-1.04 (m, 1H), 0.65-0.41 (m, 2H), 0.38-0.15(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.60; MS (ES+) 534.4 (M+1); (ES−)532.3 (M−1); Analysis calculated for C₃₀H₃₀F₃N₅O.2HCl.1.75H₂O: C, 56.47;H, 5.61; Cl, 11.11; N, 10.98; Found: C, 56.59; H, 5.45; Cl, 10.93; N,10.92.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111f) Step-1: Preparation of(3-Aminophenyl)(3-(trifluoromethyl)phenyl)methanol (111b)

To a stirred solution of 3-(trifluoromethyl) benzaldehyde (111a) (1.741g, 10 mmol) in tetrahydrofuran (5 mL) was added3-[bis(trimethylsilyl)amino]phenylmagnesium chloride solution (49c) (12mL) at 0° C. The reaction was stirred for 14 h at same temperature andquenched by adding 2 N HCl (12.50 mL), stirred for 6 h. The reactionmixture was treated with 2 N NaOH (15 mL) and extracted with ethylacetate (2×30 mL). The organic layers were combined washed withsaturated aqueous NH₄Cl (30 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with ethyl acetate in hexanefrom 0-100%) to furnish 3-(trifluoromethyl)benzaldehyde (111b) (1.121 g,42% yield) as yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.74-7.48 (m,4H), 6.94 (t, J=7.7 Hz, 1H), 6.64-6.49 (m, 2H), 6.40 (ddd, J=8.0, 2.3,1.1 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.62 (d, J=3.9Hz, 1H), 5.07 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.92; MS (ES⁺): MS (ES+) 268.2 (M+1), 290.1 (M+Na), MS (ES−) 266.15(M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111c)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.075 g, 3.82 mmol), (3-aminophenyl)(3-(trifluoromethyl)phenyl)methanol(111b) (1.022 g, 3.82 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP, 2.139 g, 4.59 mmol) was addedN,N-dimethylformamide (22 mL) and N-ethyl-N-isopropylpropan-2-amine(3.33 mL, 19.12 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere.Excess DMF was pumped-off under reduced pressure. The residue wastreated with water (30 mL), and extracted with chloroform (2×50 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue was then purified by flash columnchromatography [silica gel 40 g, eluting with methanol in chloroformfrom 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111c) (1.293 g, 2.438 mmol, 63.8% yield) as a yellow solid; MS (ES+)553.2 (M+Na); (ES−) 529.2 (M−1) which was used as such for next step.

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111c) (1.238 g, 2.334 mmol) in dichloromethane (25 mL) at 0° C. wasadded thionyl chloride (0.551 mL, 7 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (1.4 mL, 16.34 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(10 mL) and added cyclopropylmethanamine (4.0 mL, 46.7 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (50 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-100%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111d) (1.047 g, 77% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.65 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.82-7.66 (m,5H), 7.60-7.51 (m, 3H), 7.35-7.19 (m, 2H), 4.96 (s, 1H), 2.30 (dd,J=13.8, 7.0 Hz, 2H), 1.00-0.84 (m, 1H), 0.45-0.31 (m, 2H), 0.04 (td,J=5.4, 3.8 Hz, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.85, −60.96. MS(ES+) 584.3 (M+1), MS (ES−) 582.2 (M−1).

Step-4: Preparation of tert-Butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(111e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111 d) (0.996 g, 1.707 mmol) in MeOH (20 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.5 g, 6.87 mmol) and nickel(II)chloride (0.599 g, 2.52 mmol). Sodium Borohydride (0.708 g, 18.33 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.750 mL, 6.87 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(ille) (0.26 g, 16.50% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H), 7.79 (s, 1H), 7.71 (dd, J=5.3, 3.7 Hz, 1H),7.66 (t, J=1.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 3H), 7.51 (d, J=7.3 Hz, 1H),7.45-7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.24 (s,1H), 5.03-4.81 (m, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.60 (dd, J=13.6, 3.4Hz, 1H), 2.37-2.18 (m, 2H), 1.35 (s, 9H), 0.99-0.83 (m, 1H), 0.45-0.32(m, 2H), 0.09-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.85; MS (ES+)688.4 (M+1); (ES−) 686.4 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(111f)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(111e) (0.25 g, 0.364 mmol) in methanol (10 mL) was added conc. hydrogenchloride (0.757 mL, 9.09 mmol), stirred at room temperature overnightand concentrated in vacuum to dryness. The residue obtained was purifiedby flash column chromatography (silica gel 12 g, eluting with 0-50%methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111f) (0.132 g,0.225 mmol, 61.8% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.02 (s, 1H), 10.40 (s, 2H), 8.78-8.39 (m, 3H), 8.14 (s, 1H), 8.05 (d,J=7.7 Hz, 1H), 7.92 (s, 1H), 7.77-7.60 (m, 7H), 7.59-7.49 (m, 2H), 7.44(t, J=7.9 Hz, 1H), 5.75 (s, 1H), 4.12 (s, 2H), 2.69 (d, J=6.7 Hz, 2H),1.16 (dd, J=13.3, 6.6 Hz, 1H), 0.69-0.45 (m, 2H), 0.41-0.21 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.60, −60.76; MS (ES+) 588.3 (M+1); (ES−)586.3 (M−1); Analysis calculated for C₃₀H₂₇F₆N₅O₂.HCl.1.75H₂O: C, 52.07;H, 4.73; Cl, 10.25; N, 10.12; Found: C, 51.94; H, 4.60; Cl, 10.63; N,10.05.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112g) Step-1: Preparation of 4-(3-nitrobenzoyl)benzenesulfonamide(112c)

A mixture of 4-sulfamoylbenzoic acid (112b) (1 g, 4.97 mmol),3-nitrophenylboronic acid (112a) (0.996 g, 5.96 mmol),diacetoxypalladium (0.335 g, 0.497 mmol),1,1′-bis(diphenylphosphino)ferrocene (DPPF) (0.551 g, 0.994 mmol),pivalic anhydride (1.513 mL, 7.46 mmol) was degassed and purged withnitrogen, treated THF (20 mL) and water (0.224 mL, 12.43 mmol) in apositive flow of nitrogen. The reaction mixture was heated to 60° C. andstirred for 16 h at that temperature in a positive flow of nitrogen. TLCanalysis (ethyl acetate/hexanes, v/v/3/7) shows good conversion. Thereaction mixture was cooled to room temperature. Excess THF waspumped-off under reduced pressure to dryness, the obtained residue wasdiluted with saturated aqueous NH₄Cl (50 mL). The product was extractedwith ethyl acetate (2×50 mL). The combined organics layers were driedover anhydrous MgSO₄, filtered and evaporated to dryness. The residuewas purified by flash column chromatography [(silica gel 40 g, elutingwith ethyl acetate/hexanes from 0 to 50%)] to furnish4-(3-nitrobenzoyl)benzenesulfonamide (112c) (311 mg, 20% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (ddd, J=8.3, 2.4, 1.1 Hz,1H), 8.46 (t, J=2.0 Hz, 1H), 8.20 (dt, J=7.7, 1.3 Hz, 1H), 8.06-7.95 (m,4H), 7.89 (t, J=8.0 Hz, 1H), 7.63 (s, 2H, D₂O exchangeable); MS (ES⁺):MS (ES+) 329.1 (M+1), MS (ES−) 305.1 (M−1), 611.0 (2M−1); Analysiscalculated for C₁₃H₁₀N₂O₅S: C, 50.98; H, 3.29; N, 9.15; S, 10.47; Found:C, 50.93; H, 3.36; N, 9.12; S, 10.27.

Step-2: Preparation of4-((3-aminophenyl)(hydroxy)methyl)benzenesulfonamide (112d)

To a stirred solution of 4-(3-nitrobenzoyl)benzenesulfonamide (112c)(0.256 g, 0.836 mmol) in anhydrous methanol (20 mL) cooled to 0° C. wasadded nickel(II) chloride hexahydrate (0.248 g, 1.045 mmol) followed bysodium borohydride (0.253 g, 6.69 mmol) in small portions over a periodof 5 min. The reaction mixture was stirred for 45 min at 0° C., TLCanalysis (ethyl acetate/hexanes, 2/2, v/v) shows reaction was completeat this point N1-(2-aminoethyl)ethane-1,2-diamine (0.903 mL, 8.36 mmol)was added. The mixture was stirred for 30 minutes and concentrated invacuum to dryness. The residue was treated with water (50 mL), andextracted with ethyl acetate (2×50 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered and excess solvents were pumped-offunder reduced pressure. The residue was purified by flash columnchromatography [(silica gel 25 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish4-((3-aminophenyl)(hydroxy)methyl)benzenesulfonamide (112d) (136 mg, 58%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.82-7.69 (m, 2H),7.55-7.44 (m, 2H), 7.25 (s, 2H), 6.92 (t, J=7.7 Hz, 1H), 6.58-6.47 (m,2H), 6.39 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.89 (d, J=3.9 Hz, 1H, D₂Oexchangeable), 5.58 (d, J=3.8 Hz, 1H), 5.01 (s, 2H, D₂O exchangeable);MS (ES⁺): MS (ES+) 301.2 (M+Na), 579.2 (2M+Na), MS (ES−) 277.2 (M−1)555.2 (2M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112e)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.130 g, 0.462 mmol),4-((3-aminophenyl)(hydroxy)methyl)benzenesulfonamide (112d) (0.129 g,0.462 mmol), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 0.259 g, 0.555 mmol) was added N,N-dimethylformamide (3 mL) andN-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.403 mL, 2.312 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder a positive flow of nitrogen atmosphere. Excess DMF was pumped-offunder reduced pressure. The residue was treated with water (30 mL), andextracted with chloroform (2×30 mL). The combined organics were driedover anhydrous MgSO₄, filtered and evaporated to dryness. The residuewas purified by flash column chromatography [silica gel 40 g, elutingwith methanol in chloroform from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112e) (169 mg, 67% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.06-7.85 (m, 2H),7.74 (ddd, J=10.1, 7.2, 2.8 Hz, 4H), 7.64 (d, J=2.2 Hz, 1H), 7.60-7.48(m, 3H), 7.35-7.24 (m, 3H), 7.15 (d, J=7.7 Hz, 1H), 6.16 (d, J=3.8 Hz,1H, D₂O exchangeable), 5.76 (d, J=3.9 Hz, 1H); ¹H NMR (300 MHz, DMSO-d₆,D₂O) δ 10.66 (s, 1H), 8.15 (d, J=2.3 Hz, 1H), 8.04-7.87 (m, 2H),7.79-7.69 (m, 4H), 7.64 (d, J=2.1 Hz, 1H), 7.60-7.50 (m, 3H), 7.33-7.28(m, 2H), 5.76 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.95; MS (ES+)564.18 (M+1), MS (ES−) 540.2 (M−1).

Step-4: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112f)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112e) (0.164 g, 0.303 mmol) in dichloromethane (10 mL) at 0° C. wasadded thionyl chloride (0.066 mL, 0.909 mmol) and stirred at roomtemperature for 15 h. The reaction mixture was quenched withcyclopropylmethanamine (0.182 mL, 2.120 mmol) stirred for 1 h at roomtemperature, and concentrated in vacuum to dryness. The residue wasdissolved in cyclopropylmethanamine (0.519 mL, 6.06 mmol), acetonitrile(10 mL) and heated at 80° C. for 16 h. TLC analysis (CHCl₃/MeOH, 9/1,v/v) shows reaction was complete, reaction mixture was evaporated todryness. The residue was purified by flash column chromatography (silicagel 40 g, eluting with CMA80 in chloroform from 0-100%) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112f) (0.072 g, 40% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.64 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.9 Hz, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.79-7.69 (m,4H), 7.66 (s, 1H), 7.63-7.51 (m, 3H), 7.34-7.15 (m, 4H), 4.92 (s, 1H),2.28 (d, J=4.7 Hz, 3H), 0.92 (s, 1H), 0.46-0.33 (m, 2H), 0.05 (q, J=4.8Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 8.15 (t, J=1.8 Hz, 1H), 8.00(dt, J=7.7, 1.3 Hz, 1H), 7.94-7.87 (m, 1H), 7.79-7.70 (m, 4H), 7.66 (d,J=2.1 Hz, 1H), 7.63-7.51 (m, 3H), 7.33-7.17 (m, 2H), 4.91 (s, 1H), 2.28(dd, J=6.6, 2.5 Hz, 2H), 0.92 (d, J=10.4 Hz, 1H), 0.48-0.32 (m, 2H),0.05 (tt, J=5.9, 3.3 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.94; MS(ES⁺): MS (ES+) 593.24 (M+1), MS (ES−) 595.29 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112g)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112f) (0.065 g, 0.109 mmol) in anhydrous methanol (10 mL), cooled to 0°C. was added nickel(II) chloride hexahydrate (0.032 g, 0.137 mmol)followed by sodium borohydride (0.033 g, 0.875 mmol) in small portionsover 5 min. The reaction mixture was stirred for 15 min at 0° C., atthis point N₁-(2-aminoethyl)ethane-1,2-diamine (0.118 mL, 1.093 mmol)was added. The mixture was stirred for 30 minutes and concentrated invacuum to dryness. The residue was treated with water (30 mL), andextracted with chloroform (2×30 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered and excess solvents were pumped-offunder reduced pressure. The residue was purified by flash columnchromatography [(silica gel 25 g, eluting with CMA80 in chloroform from0 to 100%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(112g) (28 mg, 43% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 7.78-7.71 (m, 2H), 7.67 (t, J=1.8 Hz, 1H), 7.63-7.54 (m,3H), 7.54-7.48 (m, 2H), 7.47-7.38 (m, 2H), 7.35-7.28 (m, 1H), 7.27-7.16(m, 2H), 4.91 (s, 1H), 3.77 (s, 2H), 2.37-2.19 (m, 2H), 1.24 (s, 1H),0.93 (dd, J=8.7, 4.7 Hz, 1H), 0.52-0.27 (m, 2H), 0.10-0.01 (m, 2H); ¹HNMR (300 MHz, DMSO-d₆, D₂O) δ 7.72 (d, J=1.8 Hz, 1H), 7.70 (d, J=2.0 Hz,1H), 7.63 (t, J=1.8 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.55 (d, J=1.8 Hz,1H), 7.52-7.38 (m, 5H), 7.33-7.15 (m, 3H), 4.88 (s, 1H), 3.71 (s, 2H),2.24 (dd, J=7.0, 1.7 Hz, 2H), 0.88 (ddt, J=10.8, 7.2, 4.3 Hz, 1H),0.47-0.25 (m, 2H), 0.05-−0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.52; MS (ES⁺): MS (ES+) 599.3 (M+1), (ES−) 597.3 (M−1), 633.3 (M+Na);Analysis calculated for: C₂₉H₂₉F₃N₆O₃S.H₂O.0.15CHCl₃: C, 55.17; H, 4.95;N, 13.24; Found: C, 55.35; H, 4.66; N, 12.95.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113f) Step-1: Preparation of(3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol (113b)

To a solution of 4-(methylsulfonyl)benzaldehyde (3.68 g, 20 mmol) intetrahydrofuran (30 mL) cooled to 0° C. was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24.0 mL,24.0 mmol) stirred at 0° C. for 1 h and room temperature for 12 h. Thereaction mixture was treated with 1 N HCl (aq. 50 mL), stirred at roomtemperature for 1 h, neutralized with NaOH (2 N, aq.) to pH=˜8, andextracted with ethyl acetate (2×80 mL). The combined extracts werewashed with brine (60 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel 80 g, eluting with chloroform/methanol (1:0to 19:1)] to give (3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol(113b) (3.858 g, 70%) as a off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.88-7.81 (m, 2H), 7.64-7.58 (m, 2H), 6.93 (t, J=7.7 Hz, 1H), 6.60-6.50(m, 2H), 6.40 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 5.98 (d, J=3.8 Hz, 1H),5.62 (d, J=3.8 Hz, 1H), 5.04 (s, 2H), 3.17 (s, 3H); MS (ES+) 300.1(M+23).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-(methylsulfonyl)-phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113c)

To a solution of (3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol(113b) (2.5 g, 9.01 mmol) in DMF (48 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.53 g, 9.01 mmol), N-ethyl-N-isopropylpropan-2-amine (13.00 mL, 74.6mmol), bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 4.29 g, 9.01 mmol) and stirred at room temperature for 15 h.The reaction mixture was diluted with ethyl acetate (200 mL), washedwith water (2×80 mL), brine (80 mL), dried over MgSO₄ and concentratedin vacuum to dryness. The crude product was purified by flash columnchromatography [silica gel 80 g, eluting with hexanes/10% methanol inethyl acetate (1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113c) (4.15 g, 85%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.17-8.15 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H),7.94-7.84 (m, 3H), 7.77-7.69 (m, 2H), 7.68-7.52 (m, 4H), 7.29 (t, J=7.8Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.23 (d, J=3.8 Hz, 1H), 5.81 (d, J=3.9Hz, 1H), 3.17 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.95; MS (ES+)563.2 (M+23).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113c) (1.984 g, 3.67 mmol) in dichloromethane (50 mL) at 0° C. wasadded thionyl chloride (0.780 mL, 10.53 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was treated with triethylamine (4.50 mL, 32.3 mmol) stirred at room temperature for 1 h. It wasthen treated with cyclopropylmethanamine (5.38 g, 73.4 mmol),concentrated to remove most of dichloromethane. To the reaction wasadded acetonitrile (36 mL) heated at 70° C. for 14.5 h, and concentratedin vacuum to dryness. The residue was treated with chloroform (150 mL),washed with water (75 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel 40 g, eluting with hexanes/ethyl acetate (1:0to 1:1)] to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113d) (329 mg, 15%) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65(s, 1H), 8.18-8.13 (m, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H), 7.96-7.50 (m,9H), 7.32-7.18 (m, 2H), 4.96 (s, 1H), 3.16 (s, 3H), 2.35-2.20 (m, 2H),0.90 (d, J=7.3 Hz, 1H), 0.50-0.25 (m, 2H), 0.11-0.01 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.96; MS (ES+) 594.3 (M+1).

Step-4: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(113e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113d) (314 mg, 0.529 mmol) in MeOH (9 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (350 mg, 1.587 mmol), nickel(II)chloride hexahydrate (68.0 mg, 0.286 mmol) followed by sodiumborohydride (204 mg, 5.29 mmol) slowly over 5 min. The reaction mixturewas stirred at room temperature for 1 h, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.260 mL, 2.380 mmol) stirred atroom temperature for 0.5 h and concentrated in vacuum to dryness. Theresidue was treated with ethyl acetate (120 mL), washed with water (75mL). The aqueous phase was extracted again with ethyl acetate (75 mL).The combined organic extracts were washed with brine (75 mL), dried overMgSO₄ followed by filtration and concentration. The crude product waspurified by flash column chromatography [silica gel 4 g, eluting withchloroform/methanol (1:0 to 19:1)] to give tert-butyl3-(5-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(113e) (215 mg, 58%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69(s, 1H), 7.87-7.82 (m, 2H), 7.72-7.64 (m, 3H), 7.57 (s, 1H), 7.55-7.19(m, 8H), 4.95 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.16 (s, 3H), 2.35-2.22(m, 2H), 1.36 (s, 9H), 1.00-0.80 (m, 1H), 0.48-0.27 (m, 2H), 0.13-0.00(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78; MS (ES+) 698.4 (M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113f)

To a solution of tert-butyl 3-(5-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(113e) (0.188 g, 0.269 mmol) in 1,4-Dioxane (20 mL) was added hydrogenchloride (2.8 mL, 11.21 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 13 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 2:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(113f) (107 mg, 66%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 7.93-7.12 (m, 13H), 4.95 (s, 1H), 3.77 (s, 2H), 3.16 (s, 3H),2.36-2.21 (m, 2H), 1.01-0.82 (m, 1H), 0.47-0.31 (m, 2H), 0.13-0.02 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.53; MS (ES+): 598.3 (M+1); IR (KBrpellet, cm⁻¹): 3365, 3006, 2926, 1683, 1553, 1243, 1148; Analysiscalculated for C₃₀H₃₀F₃N₅O₃S.1.0H₂O: C, 58.53; H, 5.24; N, 11.38; Found:C, 58.85; H, 5.21; N, 11.29.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114f) Step-1: Preparation of(3-aminophenyl)(3-(methylsulfonyl)phenyl)methanol (114b)

To a stirred solution of 3-(methylsulfonyl)benzaldehyde (114a) (1 g,5.43 mmol) in tetrahydrofuran (10 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (6.51 mL,6.51 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (13.57 mL, 13.57 mmol),stirred for 6 h. The reaction mixture was treated with 2 N NaOH (15 mL)and extracted with ethyl acetate (2×50 mL). The organic layers werecombined washed with sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with ethyl acetate inhexane from 0-100%) to furnish(3-aminophenyl)(3-(methylsulfonyl)phenyl)methanol (114b) (1.004 g, 67%)as a white gum; ¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (t, J=1.7 Hz, 1H), 7.77(dt, J=7.6, 1.5 Hz, 1H), 7.66 (dt, J=7.7, 1.5 Hz, 1H), 7.57 (t, J=7.7Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.58 (t, J=1.9 Hz, 1H), 6.53 (dt,J=7.5, 1.3 Hz, 1H), 6.40 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.99 (d, J=3.8Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 5.05 (s, 2H), 3.20 (s, 3H); MS (ES+):278.1 (M+H).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114c)

In a 100 mL single-necked flask1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.963 g, 3.43 mmol), (3-aminophenyl)(3-(methylsulfonyl)phenyl)methanol(114b) (0.95 g, 3.43 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (1.629 g, 3.43 mmol) were treatedwith N,N-dimethylformamide (36.0 mL, 465 mmol) andN-ethyl-N-isopropylpropan-2-amine (DIPEA, 4.80 mL, 27.6 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred at room temperature for 16 hunder a positive flow of nitrogen atmosphere. The reaction mixture wasdiluted with ethyl acetate (120 mL), washed with water (2×60 mL) andbrine (60 mL), and dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel with hexanes/10% methanol in ethyl acetate(1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114c) (1.228 g, 66%) as a off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H),7.94 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.82-7.77(m, 1H), 7.76-7.64 (m, 4H), 7.63-7.55 (m, 2H), 7.30 (t, J=7.8 Hz, 1H),7.18 (dt, J=7.7, 1.3 Hz, 1H), 6.24 (d, J=3.9 Hz, 1H), 5.82 (d, J=3.9 Hz,1H), 3.18 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.98; MS (ES−): 539.2(M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114c) (1.18 g, 2.19 mmol) in dichloromethane (25 mL) at 0° C. was addedthionyl chloride (1.06 mL, 14.55 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was quenched triethyl amine (2.70 mL,19.34 mmol), stirred for 1 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(22 mL) and added cyclopropylmethanamine (3.21 g, 43.8 mmol). Thereaction mixture was heated at 70° C. for 19 h, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in chloroform (120 mL), washed with water (60 mL), dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel 40 g, eluting 0-50% ethylacetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114d) (208 mg, 16%) as a yellow solid, ¹H NMR (300 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.16 (t, J=1.9 Hz, 1H), 8.06-7.98 (m, 2H), 7.95-7.87 (m,1H), 7.80-7.51 (m, 7H), 7.33-7.18 (m, 2H), 4.97 (s, 1H), 3.17 (s, 3H),2.36-2.22 (m, 2H), 1.02-0.79 (m, 1H), 0.55-0.29 (m, 2H), 0.17-−0.02 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.94; MS (ES+): 594.3 (M+1).

Step-4: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)-methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(114e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114d) (195 mg, 0.328 mmol) in MeOH (6 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (217 mg, 0.985 mmol) and nickel(II)chloride (42.0 mg, 0.177 mmol). Sodium borohydride (127 mg, 3.28 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.160 mL, 1.462 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in ethyl acetate (60 mL) and water (60 mL). The aqueous phasewas separated and extracted again with ethyl acetate (60 mL). Theorganic extracts were combined, washed with brine (60 mL), dried overMgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography [silica gel 4 g,eluting with chloroform/methanol (1:0 to 19:1)] to give tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(114e) (135 mg, 59%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 8.00 (bs, 1H), 7.79-7.71 (m, 2H), 7.68 b (s, 1H), 7.61-7.19 (m,10H), 4.96 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.16 (s, 3H), 2.33-2.22 (m,2H), 1.36 (s, 9H), 0.99-0.80 (m, 1H), 0.46-0.31 (m, 2H), 0.10-0.00 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.78; MS (ES+): 698.4 (M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114f)

To a solution of tert-butyl 3-(5-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(114e) (120 mg, 0.172 mmol) in 1,4-Dioxane (15 mL) was added hydrogenchloride (1.8 mL, 7.2 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 15 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel elutingwith chloroform/CMA80 (1:0 to 2:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(114f) (49 mg, 48%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.94 (s, 1H), 10.17 (s, 2H), 8.46-7.37 (m, 13H), 5.81 (s, 1H), 4.13 (d,J=5.1 Hz, 2H), 3.22 (s, 3H), 2.83-2.67 (m, 2H), 1.13 (bs, 1H), 0.56 (d,J=7.8 Hz, 2H), 0.31 (bs, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS(ES+): 598.3 (M+1); IR (KBr pellet, cm⁻¹): 3433, 3013, 1675, 1616, 1558,1246, 1143.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (115e)Step-1: Preparation of tert-butyl3-(5-((3-(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115a)

To a solution of tert-butyl3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(18c) (133 mg, 0.235 mmol) in dichloromethane (5 mL) at 0° C. was addedtriethylamine (0.131 mL, 0.939 mmol), thionyl chloride (0.026 mL, 0.352mmol) and stirred at room temperature for 2 h. The reaction mixture wasconcentrated in vacuum to dryness to furnish tert-butyl3-(5-(3-(chloro(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115a) (137 mg, 100%) which was used as such for next step.

Step-2: Preparation of tert-butyl3-(5-((3-(azido(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115b)

To a stirred solution of tert-butyl3-(5-(3-(chloro(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115a) (137 mg, 0.235 mmol) in acetonitrile (10 mL) was added sodiumazide (61.1 mg, 0.94 mmol) and heated at reflux for 16 h. The reactionmixture was concentrated in vacuum, diluted with ethyl acetate (25 mL),and washed with water (2×10 mL). The aqueous layer was extracted withethyl acetate (2×25 mL). The organic layers were combined washed withwater (20 mL), brine (10 mL), dried and concentrated in vacuum. Thecrude residue was purified by flash column chromatography (silica gel, 4g eluting with ethyl acetate in hexanes 0-100%) to afford tert-butyl3-(5-(3-(azido(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115b) (75 mg, 0.127 mmol, 53.9% yield) as a colorless solid; MS (ES+)614.3 (M+Na), 590.3 (ES−) (M−1).

Step-3: Preparation of tert-butyl3-(5-((3-(amino(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115c)

To a suspension of Pd/C (10%, 12.59 mg) in methanol (20 mL) was addedtert-butyl3-(5-(3-(azido(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115b) (70 mg, 0.118 mmol) and hydrogenated at 60 psi for 2 h. Thereaction mixture was filtered through celite and concentrated in vacuum.The crude residue was purified by flash column chromatography (silicagel, 4 g eluting with CMA 80 in chloroform 0 to 100%) to affordtert-butyl3-(5-(3-(amino(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115c) (24 mg, 35.9% yield) as a colorless foam; MS (ES+) 566.3 (M+1);(ES−) 564.3 (M−1).

Step-4: Preparation of tert-butyl3-(5-((3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115d)

To a solution of tert-butyl3-(5-(3-(amino(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115c) (24 mg, 0.042 mmol) in dichloromethane (5 mL) was addedcyclopropanecarboxylic acid (5.07 μL, 0.064 mmol), triethylamine (0.024mL, 0.170 mmol) and EDCI (16.27 mg, 0.085 mmol) at room temperature. Theresulting reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was diluted with water (20 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried, filtered and concentrated invacuum. The crude residue was purified by flash column chromatography(silica gel 12 g, eluting with ethyl acetate in hexanes 0 to 100%) toafford tert-butyl3-(5-(3-(cyclopropanecarboxamido(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115d) (23 mg, 0.036 mmol, 86% yield); MS (ES+) 656.4 (M+Na); (ES−)632.3 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (115e)

To a solution of tert-butyl3-(5-(3-(cyclopropanecarboxamido(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(115d) (21 mg, 0.033 mmol) in methanol (5 mL) was added conc. hydrogenchloride (0.033 mL, 0.133 mmol), stirred at room temperature overnightand concentrated in vacuum to dryness. The residue obtained was purifiedby flash column chromatography (silica gel 4 g, eluting with 0-50%methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(115e) (0.016 g, 0.030 mmol, 90% yield) as a white solid; ¹HNMR (300MHz, DMSO) δ 10.78 (s, 1H), 9.02 (d, J=8.7 Hz, 1H), 8.30 (s, 3H), 7.71(s, 1H), 7.64 (s, 1H), 7.62-7.54 (m, 3H), 7.52 (q, J=2.1 Hz, 2H),7.39-7.30 (m, 3H), 7.27 (d, J=7.1 Hz, 3H), 7.04 (d, J=7.6 Hz, 1H), 6.69(s, 1H), 6.08 (d, J=8.4 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 0.68 (s, 2H),0.66 (s, 2H); MS (ES+) 534.4 (M+1); (ES−) 532.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-ethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116e) Step-1: Preparation of (3-aminophenyl)(3-vinylphenyl)methanol(116b)

To a stirred solution of 3-vinylbenzaldehyde (116a) (1.32 g, 10 mmol) intetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-aminophenyl)-(3-vinylphenyl) methanol (116b) (1.2g, 53.33% yield) as a red brown oil, which was used as such for nextstep.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.947 g, 6.924 mmol) in toluene (50 mL) and DMF 15 drops was addedSOCl₂ (0.928 mL, 12.78 mmol) at 0° C. Reaction was refluxed for 3.5 hrand concentrated to remove volatile solvent. The residue obtained wasdissolved in DCM (50 mL) and added(3-Amino-phenyl)-(3-vinyl-phenyl)-methanol (116b) (1.2 g, 5.326 mmol),triethylamine (7.2 mL) at room temperature. Reaction mixture was stirredovernight at room temp. Reaction mixture was concentrated and purifiedby flash column chromatography (silica gel, eluting with 10%-70% ethylacetate in hexane) to afford product2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(3-vinyl-phenyl)-methyl]-phenyl}-amide (116c) (2.1 g,80.76%) as a red-brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.63(s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.89(ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=1.7Hz, 1H), 7.64 (t, J=1.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.35-7.22 (m, 4H), 7.15 (d, J=7.6 Hz, 1H), 6.71 (dd, J=17.7,10.9 Hz, 1H), 5.97 (d, J=3.9 Hz, 1H), 5.78 (dd, J=17.6, 1.1 Hz, 1H),5.68 (d, J=3.9 Hz, 1H), 5.24 (dd, J=11.0, 1.0 Hz, 1H).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116c) (2.1 g, 4.299 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.65 mL, 8.598 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (50 mL) and addedcyclopropylmethanamine (5.6 mL, 64.485 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum to afford1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116d) (4.9 g) as a red-brown sticky liquid, which was used as suchwithout further purification.

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-ethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116e)

To a solution of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116d) (4.9 g crude, 8.986 mmol) in MeOH (50 mL) cooled with ice/waterwas added nickel(II) chloride hexahydrate (2.67 g, 11.233 mmol) followedby portionwise addition of sodium borohydride (2.03 g, 53.916 mmol) overa period of 15 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (4.85 mL,44.92 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness and the residue obtainedwas dissolved in chloroform (25 mL) and water (25 mL). The aqueous layerwas separated extracted with chloroform (25 mL). The combined extractswere washed with brine (25 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting with 0-25%chloroform/methanol) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-ethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(116e) (0.041 g; 1% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.74 (s, 1H), 7.70 (d, J=6.3 Hz, 2H), 7.67 (s, 1H), 7.63-7.49 (m, 4H),7.28-7.17 (m, 5H), 7.04 (q, J=3.2, 2.7 Hz, 1H), 4.83 (s, 1H), 4.11 (s,2H), 2.56 (d, J=7.7 Hz, 2H), 2.29 (dd, J=7.8, 5.1 Hz, 2H), 1.15 (t,J=7.6 Hz, 3H), 1.01-0.86 (m, 1H), 0.46-0.35 (m, 2H), 0.06 (q, J=4.9 Hz,2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.79; MS (ES+) 548.3 (M+1); (ES−)546.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(117e) Step-1: Preparation of (3-aminophenyl)(2-fluorophenyl)methanol(117b)

To a stirred solution of 2-fluorobenzaldehyde (117a) (1.32 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.5 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish (3-aminophenyl)(2-fluorophenyl)methanol(117b) (1.8 g, 77.92% yield) as a red-brown oil.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(117c)

To a stirred solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid(117b) (3.02 g, 10.770 mmol) in toluene (50 mL) and DMF 15 drops wasadded SOCl₂ (2.365 g, 19.88 mmol) at 0° C. Reaction was refluxed for 3.5hr and concentrated to remove volatile solvent. The residue obtained wasdissolved in dichloromethane (100 mL) and added(3-amino-phenyl)-(2-fluoro-phenyl)-methanol (117b) (1.8 g, 8.284 mmol)was added followed by dropwise addition of triethylamine (10.8 mL) atroom temperature. Reaction mixture was stirred overnight at room tempconcentrated in vacuum to dryness. The residue obtained was purified byflash chromatography (10%-70% ethyl acetate in hexane) to afford product2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-fluoro-phenyl)-hydroxy-methyl]-phenyl}-amide (117c) (2.1 gm) as ared-brown liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.21 (t,J=1.8 Hz, 1H), 8.05 (dt, J=7.8, 1.3 Hz, 1H), 7.95 (ddd, J=8.2, 2.1, 1.1Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.69-7.53 (m,3H), 7.38-7.29 (m, 2H), 7.25 (td, J=7.5, 1.3 Hz, 1H), 7.21-7.12 (m, 2H),6.12 (d, J=4.2 Hz, 1H), 5.98 (d, J=4.2 Hz, 1H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(117d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-fluoro-phenyl)-hydroxy-methyl]-phenyl}-amide (117c) (2.1 g, 4.371mmol) in dichloromethane (50 mL) at 0° C. was added thionyl chloride(0.65 mL, 8.742 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (50 mL) and addedcyclopropylmethanamine (5.7 mL, 65.568 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(117d) (1.05 g, 45.06% yield) as a red-brown sticky liquid.

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(117e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(117d) (1.05 g, 1.968 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.584 g, 2.46 mmol) followed byportionwise addition of sodium borohydride (0.45 g, 11.808 mmol) over aperiod of 15 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.06 mL,9.84 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness and the residue obtainedwas dissolved in chloroform (25 mL) and water (25 mL). The aqueous layerwas separated extracted with chloroform (25 mL). The combined extractswere washed with brine (25 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting with 0-25%chloroform/methanol) to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(117e) (0.29 g, 27.43% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.78 (s, 1H), 8.37 (s, 3H), 7.72 (s, 1H), 7.70-7.56 (m, 5H),7.56-7.47 (m, 1H), 7.28 (t, J=7.8 Hz, 2H), 7.22 (s, 2H), 7.12 (dd,J=10.7, 8.2 Hz, 1H), 5.17 (s, 1H), 4.12 (s, 2H), 2.34 (d, J=6.7 Hz, 2H),0.94 (d, J=11.1 Hz, 1H), 0.48-0.35 (m, 2H), 0.12-0.02 (m, 2H); ¹⁹F NMR(282 MHz, DMSO d₆) δ −60.79, −118.99; MS (ES+) 538.3 (M+1); (ES−) 536.3(M−1); Analysis calculated for C₃₀H₃₀F₃N₅02.2.75HCl: C, 54.61; H, 4.70;N, 10.98; Found: C, 54.63; H, 4.50; N, 11.17.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118f) Step-1: Preparation of(3-aminophenyl)(10-chloroanthracen-9-yl)methanol (118b)

To a stirred solution of 10-chloroanthracene-9-carbaldehyde (118a) (2 g,8.31 mmol) in tetrahydrofuran (20 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (2.95 g,9.97 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (10.39 mL, 20.77 mmol),stirred for 2 h. The reaction mixture was treated with 2 N NaOH (12.46mL, 24.93 mmol) and extracted with ethyl acetate (2×50 mL). The organiclayers were combined washed with sat. NH₄Cl (50 mL), dried overanhydrous MgSO₄, filtered, evaporated to dryness. The crude residue waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexane) to furnish(3-aminophenyl)(10-chloroanthracen-9-yl)methanol (118b) (2.375 g, 7.11mmol, 86% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d,J=9.0 Hz, 2H), 8.49 (dd, J=8.8, 1.2 Hz, 2H), 7.78-7.60 (m, 2H), 7.53(dd, J=8.9, 6.6 Hz, 2H), 7.16 (d, J=4.3 Hz, 1H), 6.90 (t, J=7.8 Hz, 1H),6.52-6.47 (m, 1H), 6.41 (s, 1H), 6.38-6.31 (m, 2H), 4.91 (s, 2H, D₂Oexchangeable); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 8.61 (d, J=9.0 Hz, 2H),8.51 (dd, J=8.7, 1.2 Hz, 2H), 7.69 (ddd, J=8.9, 6.5, 1.1 Hz, 2H), 7.54(dd, J=8.9, 6.6 Hz, 2H), 7.16 (s, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.55-6.43(m, 2H), 6.37 (dd, J=7.7, 2.2 Hz, 1H); MS (ES−): MS (ES−) 332.3 (M−1).

Step-2: Preparation ofN-(3-((10-chloroanthracen-9-yl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118c)

To a single-necked 100 mL flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.264 g, 4.49 mmol), (3-aminophenyl)(10-chloroanthracen-9-yl)methanol(118b) (1.5 g, 4.49 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 2.51 g, 5.39 mmol) was addedN,N-dimethylformamide (26.1 mL, 337 mmol),N-ethyl-N-isopropylpropan-2-amine (3.91 mL, 22.47 mmol) successively ina positive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. Excess DMF was pumped-off under reducedpressure. The residue was treated with water (75 mL) extracted withchloroform (2×75 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered and evaporated to dryness. The residue waspurified by flash column chromatography [silica gel 40 g, eluting withethyl acetate in hexanes from 0-100%] to furnishN-(3-((10-chloroanthracen-9-yl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118c) (1.823 g, 68.0% yield) as a yellow solid.

MS (ES−) 595.2 (M−1).

Step-3: Preparation ofN-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118d)

To a solution ofN-(3-((10-chloroanthracen-9-yl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118c) (1.685 g, 2.82 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.618 mL, 8.47 mmol) and stirred at roomtemperature for 18 h. The reaction mixture was quenched withcyclopropylmethanamine (1.693 mL, 19.76 mmol) stirred for 1 h at roomtemperature, and concentrated in vacuum to dryness. The residue wasdissolved in cyclopropylmethanamine (4.84 mL, 56.5 mmol) andacetonitrile (20 mL) and the reaction mixture was heated at 80° C. for16 h TLC analysis (ethyl acetate/hexanes, 3/7, v/v) shows reaction wascomplete; reaction mixture was evaporated to dryness. The residue waspurified by flash column chromatography (silica gel 40 g, eluting 0-100%ethyl acetate in hexanes from 0-100%) to affordN-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118d) (0.903 g, 1.389 mmol, 49.2% yield) as a yellow solid.

MS (ES+) 649.19 (M−1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118f)

To a stirred solution ofN-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118d) (831 mg, 1.278 mmol) in anhydrous methanol (20 mL), cooled to 0°C. was added, di-tert-butyl dicarbonate (0.837 g, 3.83 mmol), nickel(II)chloride hexahydrate (0.380 g, 1.598 mmol) followed by sodiumborohydride (0.283 g, 7.668 mmol) in small portions over a period of 5min. The reaction was exothermic and effervescent. The reaction mixturewas stirred for 45 min at 0° C., at this pointN1-(2-aminoethyl)ethane-1,2-diamine (1.381 mL, 12.78 mmol) was added.The mixture was allowed to stir for 30 mins and concentrated in vacuumto dryness. The residue was treated with water (50 mL), and extractedwith chloroform (2×50 mL). The organic layers were combined dried overanhydrous MgSO₄; filtered and excess solvents were pumped-off underreduced pressure. The residue was purified by flash columnchromatography [(silica gel 40 g, eluting with methanol/chloroform from0 to 100%)] to furnish tert-butyl3-(5-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(118e) (0.463 g, 0.614 mmol, 48.0% yield) as a yellow solid and1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118f) (0.143 g, 0.219 mmol, 17.10% yield) which was isolated as afree-base. Free base of compound 118f was treated with aqueous 12 N HCl(7 eq, 0.13 mL) in 2 mL of IPA and stirred for 10 min, then trituratedwith ether, refluxed for 1 h, cooled to room temperature. The solidobtained was collected by filtration dried under reduced pressure for 16h to afford1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(118f) (50 mgs) hydrochloride salt as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.79 (s, 1H), 10.66 (s, 1H), 9.79 (s, 1H), 8.83-8.57 (m,3H), 8.40 (s, 3H), 8.20 (m, 1H), 7.79 (m, 4H), 7.66-7.45 (m, 6H), 7.24(m, 1H), 7.15 (s, 1H), 4.09 (q, J=5.8 Hz, 2H), 3.03 (m, 1H), 2.64 (m,1H), 1.21-1.07 (m, 1H), 0.47 (m, 2H), 0.33-0.12 (m, 2H); ¹⁹F NMR (282MHz, DMSO) δ −60.86; MS (ES+) 654.3 (M+1); (ES−) 652.3 (M−1); Analysiscalculated for C₃₇H₃₁ClF₃N₅O.2.25HCl.2H₂O: C, 57.55; H, 4.86; Cl, 14.92;N, 9.07; Found: C, 57.29; H, 4.96; Cl, 14.96; N, 8.87.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119e) Step-1: Preparation of (3-aminophenyl)(2-methoxyphenyl)methanol(119b)

To a stirred solution of 2-methoxybenzaldehyde (119a) (1.36 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish (3-aminophenyl)(2-methoxyphenyl)methanol(119b) (0.8 g, 35% yield) as a red-brown oil.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119c)

To a stirred solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (9i)(1.275 g, 4.536 mmol) in toluene (50 mL) and DMF 15 drops was addedSOCl₂ (0.618 mL, 12.78 mmol) at 0° C. Reaction was refluxed for 3.5 hrand concentrated to remove volatile solvent. The residue obtained wasdissolved in DCM (100 mL) and (3-aminophenyl)(2-methoxyphenyl)methanol(119b) (0.8 g, 3.5 mmol) was added followed by dropwise addition oftriethylamine (4.8 mL) at RT. Reaction mixture was stirred overnight atroom temp and concentrated in vacuum to dryness. The residue obtainedwas purified by flash chromatography (10%-70% ethyl acetate in hexane)to afford1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119c) (1.8 g, 80.76%) as a red-brown oil which solidified on standing;¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.20 (t, J=1.9 Hz, 1H), 8.05(dt, J=7.8, 1.3 Hz, 1H), 7.95 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 (d,J=8.0 Hz, 1H), 7.76 (s, 1H), 7.69 (t, J=1.9 Hz, 1H), 7.61-7.54 (m, 1H),7.49 (dd, J=7.8, 1.8 Hz, 1H), 7.32-7.22 (m, 2H), 7.19-7.11 (m, 1H),7.03-6.94 (m, 2H), 6.03 (d, J=4.1 Hz, 1H), 3.80 (s, 3H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(119d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119c) (1.8 g, 3.655 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.87g, 7.310 mmol) and stirred at room temperature for4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (50 mL) and addedcyclopropylmethanamine (3.9 g, 54.82 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained (4.2 gm crude) of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(119d) as a red brown oil was used as such for next step.

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(2-fluoro-phenyl)-methyl]-phenyl}-amide(119d) (4.2 gm crude) in MeOH (50 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (2.28 g, 9.628 mmol) followed byportionwise addition of sodium borohydride (1.748g, 46.212 mmol) over aperiod of 15 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (4.85 mL,44.92 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness and the residue obtainedwas dissolved in chloroform (25 mL) and water (25 mL). The aqueous layerwas separated extracted with chloroform (25 mL). The combined extractswere washed with brine (25 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting with 0-25%chloroform/methanol) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119e) (210 mgs, 10%) as a white solid. The solid was repurified byflash column chromatography (silica gel 4 g, eluting with 0-25%chloroform/methanol) to furnish product which was dissolved in methanoladded 10 eq of conc. HCL and concentrated in vacuum to dryness tofurnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(119e) (10 mg) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.04 (s, 1H), 9.72 (s, 1H), 8.49 (s, 3H), 7.84 (t, J=1.8 Hz, 1H), 7.78(dd, J=7.8, 1.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.70 (s, 1H), 7.66-7.60(m, 2H), 7.59-7.48 (m, 3H), 7.45-7.33 (m, 2H), 7.06 (ddd, J=14.9, 7.9,1.0 Hz, 2H), 5.74 (s, 1H), 4.12 (s, 2H), 3.82 (s, 3H), 2.81-2.67 (m,2H), 1.20-0.99 (m, 1H), 0.62-0.49 (m, 2H), 0.32-0.20 (m, 2H); 19F NMR(282 MHz, DMSO-d₆) δ −60.79; MS (ES+) 550.04 (M+1); (ES−) 548.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120e) Step-1: Preparation of (3-aminophenyl)(4-isopropylphenyl)methanol(120b)

To a stirred solution of 4-isopropylbenzaldehyde (120a) (1.48 g, 10mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (4-aminophenyl)(4-isopropylphenyl)methanol (120b)(1.85 g, 81% yield) as a red-brown sticky liquid.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120c)

To a stirred solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (9i)(2.726 g, 9.696 mmol) in toluene (50 mL) and DMF 15 drops was addedSOCl₂ (2.129 g, 17.900 mmol) at 0° C. Reaction was refluxed for 3.5 hrand concentrated to remove volatile solvent. The residue obtained wasdissolved in DCM (100 mL) and (3-aminophenyl)(4-isopropylphenyl)methanol(120b) (1.85 g, 7.46 mmol) was added followed by dropwise addition ofTriethylamine 7.2 mL) at RT. Reaction mixture was stirred overnight atroom temp concentrated in vacuum to dryness. The residue obtained waspurified by flash chromatography (10%-70% ethyl acetate in hexane) toafford1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120c) (3.1 g, 82.44%) as a red-brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78-7.69 (m, 2H), 7.64 (t,J=1.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.31-7.22 (m, 3H), 7.15 (dd, J=8.5,6.8 Hz, 3H), 5.86 (d, J=3.7 Hz, 1H), 5.63 (d, J=3.7 Hz, 1H), 2.83 (p,J=6.9 Hz, 1H), 1.16 (d, J=7.0 Hz, 6H).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120c) (3.8 g, 7.53 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride 0.89 mL, 12.288 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (50 mL) and addedcyclopropylmethanamine (8.0 mL, 92.17 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120d) (1.05 g, 30.64% yield) as a red-brown sticky liquid which wasused as such for next step.

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120e)

To a solution of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120d) (1.05 g, 1.883 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.559 g, 2.353 mmol) followed byportionwise addition of Sodium Borohydride (0.427 g, 11.298 mmol) over aperiod of 15 min. The reaction mixture was stirred at room temperaturefor 1 h and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (1.2 mL,11.83 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness and the residue obtainedwas dissolved in chloroform (25 mL) and water (25 mL). The aqueous layerwas separated extracted with chloroform (25 mL). The combined extractswere washed with brine (25 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting with 0-25%chloroform/methanol) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120e) (168 mg, 16% yield) free base as a white solid. The solid wasrepurified by flash column chromatography (silica gel 4 g, eluting with0-25% chloroform/methanol) to furnish product (120e) as a free base,which was dissolved in methanol added 10 equi of conc. HCL andconcentrated in vacuum to dryness to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(120e) (10 mg) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H),10.07 (s, 2H), 8.52 (s, 3H), 7.88 (t, J=1.8 Hz, 1H), 7.72 (d, J=3.6 Hz,2H), 7.69-7.49 (m, 7H), 7.43 (t, J=7.9 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H),5.58-5.44 (m, 1H), 4.12 (q, J=5.7 Hz, 2H), 2.87 (p, J=6.9 Hz, 1H), 2.70(q, J=6.1 Hz, 2H), 1.26-1.08 (m, 7H), 0.59-0.49 (m, 2H), 0.35-0.25 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+) 562.4 (M+1); (ES−) 560.4(M−1); Analysis calculated for C₃₂H₃₄F₃N₅O.1.95HCl.1.75H₂O: C, 57.86; H,5.99; Cl, 10.41; N, 10.54; Found: C, 58.01; H, 6.02; Cl, 10.03; N,10.06.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121f) Step-1: Preparation of(3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol (121b)

To a solution of 2-(methylsulfonyl)benzaldehyde (121a) (3.80 g, 20 mmol)in tetrahydrofuran (30 mL) was cooled to 0° C. was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24.00 mL,24.00 mmol) and stirred at room temperature for 12 h. The reactionmixture was treated with 1 N HCl (aq. 50 mL), stirred at RT for 1 h,neutralized with NaOH (2 N, aq.) to pH=˜8, and extracted with ethylacetate (2×80 mL). The combined extracts were washed with brine (60 mL),dried over MgSO₄ followed by filtration and concentration. The crudeproduct was purified by flash column chromatography [silica gel 80 g,eluting with chloroform/methanol (1:0 to 19:1)] to give(3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol (121b) (4.912 g, 89%)as a white foam; ¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (dd, J=7.9, 1.4 Hz,1H), 7.73-7.47 (m, 3H), 6.94 (t, J=7.7 Hz, 1H), 6.60-6.55 (m, 2H), 6.48(dt, J=7.4, 1.2 Hz, 1H), 6.41 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 6.00 (d,J=5.0 Hz, 1H), 5.04 (s, 2H), 3.13 (s, 3H); MS (ES+): 300.2 (M+Na).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121c)

To a solution of (3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol(121b) (3.46 g, 12.48 mmol) in DMF (60 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(3.51 g, 12.48 mmol), N-ethyl-N-isopropylpropan-2-amine (18.00 mL, 103mmol), bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 5.93 g, 12.48 mmol) and stirred at room temperature for 15 h.The reaction mixture was diluted with ethyl acetate (240 mL), washedwith water (2×100 mL) brine (100 mL), dried over MgSO₄ followed byfiltration and concentration. The crude product was purified by flashcolumn chromatography [silica gel 120 g, eluting with hexanes/10%methanol in ethyl acetate (1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121c) (5.302 g, 79%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.67 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H),7.97-7.87 (m, 2H), 7.77-7.49 (m, 7H), 7.28 (t, J=7.9 Hz, 1H), 7.10 (d,J=7.7 Hz, 1H), 6.71 (d, J=4.9 Hz, 1H), 6.28 (d, J=4.9 Hz, 1H), 3.23 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.94; MS (ES+): 563.2 (M+Na).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121c) (3.407 g, 6.30 mmol) in dichloromethane (80 mL) at 0° C. wasadded thionyl chloride (1.2 mL, 16.21 mmol) and stirred at roomtemperature for 2 h. the reaction mixture was treated with triethylamine (7.00 mL, 50.2 mmol) and stirred at room temperature for 1 h. Itwas then treated with cyclopropylmethanamine (8.45 mL, 95 mmol) andconcentrated to remove most of dichloromethane followed by addition ofacetonitrile (60 mL), stirring at 70° C. for 13 h, and reflux for 5 h.The reaction mixture was treated with additional cyclopropylmethanamine(5 mL, 55.92 mmol), refluxed for 14 h, and concentrated to dryness. Theresidue was treated with chloroform (240 mL), washed with water (100mL), dried over MgSO₄ followed by filtration and concentration. Thecrude product was purified by flash column chromatography [silica gel 80g, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to give1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121d) (976 mg, 26%) as a brown gum. ¹H NMR (300 MHz, DMSO-d₆) δ 10.68(s, 1H), 8.18-8.15 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.95 (dd,J=7.9, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.77-7.46 (m,7H), 7.36-7.22 (m, 2H), 5.95 (d, J=4.9 Hz, 1H), 3.28 (s, 3H), 2.75-2.60(m, 1H), 2.30-2.14 (m, 1H), 0.98-0.80 (m, 1H), 0.47-0.26 (m, 2H),0.16-−0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.94; MS (ES+): 594.3(M+H).

Step-4: Preparation of tert-butyl3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(121e)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121d) (700 mg, 1.179 mmol) in MeOH (20 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (780 mg, 3.54 mmol), nickel chloridehexahydrate (0.3 mmol), followed by sodium borohydride (455 mg, 11.79mmol) slowly over 5 min. The reaction mixture was stirred for 1 h,treated with N1-(2-aminoethyl)ethane-1,2-diamine (0.570 mL, 5.22 mmol),stirred at room temperature for 0.5 h and concentrated in vacuum todryness. The residue was treated with ethyl acetate (150 mL), washedwith water (75 mL). The aqueous phase was extracted again with ethylacetate (75 mL). The combined extracts were washed with brine (75 mL),dried over MgSO₄ followed by filtration and concentration. The crudeproduct was purified by flash column chromatography [silica gel 12 g,eluting with hexanes/ethyl acetate (1:0 to 2:1), thenchloroform/methanol (1:0 to 9:1)] to give tert-butyl3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(121e) (368 mg, 45%) as a white foam; ¹H NMR (300 MHz, DMSO-d₆) δ 10.64(s, 1H), 7.93-7.87 (m, 1H), 7.66-7.16 (m, 13H), 5.89 (s, 1H), 4.14 (d,J=6.3 Hz, 2H), 3.22 (s, 3H), 2.44-2.36 (m, 1H), 2.25-2.10 (m, 1H), 1.31(s, 9H), 0.93-0.70 (m, 1H), 0.42-0.22 (m, 2H), 0.09-−0.07 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.62; MS (ES+): 698.4 (M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121f)

To a solution of tert-butyl 3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(121e) (0.344 g, 0.493 mmol) in 1,4-Dioxane (40 mL) was added hydrogenchloride (5.2 mL, 20.8 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 17 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel, elutingwith chloroform/CMA80 (1:0 to 2:1)] to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121e) as a free base. The purified product 121e was dissolved inmethanol (10 mL) and treated with 4 N HCl (aq. 0.45 mL) followed byconcentration to dryness to give1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(121e) (224 mg, 68%) hydrochloride salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.96 (s, 1H), 10.27 (s, 1H), 10.13 (s, 1H), 8.33 (s,3H), 8.24 (d, J=8.2 Hz, 1H), 8.07 (dd, J=7.9, 1.4 Hz, 1H), 7.94-7.87 (m,1H), 7.84 (s, 1H), 7.76-7.66 (m, 3H), 7.66-7.53 (m, 3H), 7.53-7.44 (m,2H), 6.62 (d, J=7.0 Hz, 1H), 4.13 (q, J=5.9 Hz, 2H), 3.25 (s, 3H),3.02-2.64 (m, 2H), 1.09 (t, J=7.0 Hz, 1H), 0.58 (t, J=7.4 Hz, 2H), 0.33(s, 2H); ¹H NMR (D₂O ex NMR, 300 MHz, DMSO-d₆) δ 8.13-7.39 (m, 13H),6.59 (s, 1H), 4.13 (s, 2H), 3.22 (s, 3H), 3.00-2.88 (m, 1H), 2.81-2.67(m, 1H), 1.15-0.95 (m, 1H), 0.67-0.50 (m, 2H), 0.37-0.22 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+): 598.3 (M+1); IR (KBr pellet,cm⁻¹): 3433, 3015, 1672, 1612, 1553, 1246, 1149; Analysis calculated forC₃₀H₃₀F₃N₅O₃S.2HCl.2H₂O: C, 50.99; H, 5.14; N, 9.91; Found: C, 50.86; H,5.03; N, 9.73.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122g) Step-1: Preparation of (4-aminophenyl)(p-tolyl)methanol (122b)

To a stirred solution of 4-methylbenzaldehyde (122a) (1.2 g, 10 mmol) intetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.50 mL), stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish (3-aminophenyl)(2-methoxyphenyl)methanol(122b) (1.5 g, 65% yield) as a gray powder.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122c)

To a stirred solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (9i)(2.57 g, 9.142 mmol) in toluene (50 mL) and DMF 15 drops was added SOCl₂(2.0 g, 16.879 mmol) at 0° C. Reaction was refluxed for 3.5 hr andconcentrated to remove volatile solvent. The residue obtained wasdissolved in DCM (100 mL) and (4-aminophenyl)(2-methoxyphenyl)methanol(122b) (1.5 g, 7.033 mmol) was added followed by dropwise addition oftriethylamine (7.2 mL) at RT. Reaction mixture was stirred overnight atroom temp concentrated in vacuum to dryness. The residue obtained waspurified by flash chromatography (10%-70% ethyl acetate in hexane) toafford1-(3-cyanophenyl)-N-(3-(hydroxy(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122c) (1.8 g, 53.7%) as a brown sticky liquid.

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122c) (1.8 g, 3.777 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.6 mL, 7.555 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (50 mL) and addedcyclopropylmethanamine (4.9 mL, 56.669 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122d) (1.1 g, 55% yield) as a brown sticky liquid.

Step-4: Preparation of tert-butyl3-(5-((3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(122e) and tert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(p-tolyl)methyl)(cyclopropylmethyl)carbamate(122f)

To a solution of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122d) (1.1 g, 2.077 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.542 g, 2.284 mmol) and Bocanhydride (2.4 mL, 10.385 mmol) followed by portionwise addition ofSodium Borohydride (0.94 g, 24.926 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 20 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (1.1 mL, 10.385 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% chloroform/methanol) to furnishtert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(p-tolyl)methyl)(cyclopropylmethyl)carbamate(0.214 gm) (122f) (0.214 g) as a white solid and tert-butyl3-(5-((3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(122e) (0.445 gm) as a white solid.

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122g)

A solution of tert-butyl3-(5-((3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(122e) (0.445 g, 0.702 mmol) and tert-butyl((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(p-tolyl)methyl)(cyclopropylmethyl)carbamate(122f) (0.214 g, 0.337 mmol) were dissolved separately in methanol (2.5mL) and added conc. HCL (1.0 mL). The reaction mixture was stirred atroom temperature overnight and concentrated in vacuum to dryness. Theresidue was azeotroped with toluene (2×10 mL) and ethanol (10 mL), driedin vacuum pump to furnish a white solid residue. NMR of the residue inmethanol and TLC shows same compound. The products were combined driedand purified by flash column chromatography (silica gel 12 g, elutingwith 0-150% methanol in dichloromethane to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(p-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(122g) (0.2 g, 36.1%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H), 10.19-10.00 (m, 2H), 8.55 (d, J=5.7 Hz, 3H), 7.88-7.82(m, 1H), 7.73 (d, J=2.4 Hz, 2H), 7.64 (dq, J=7.8, 2.3 Hz, 3H), 7.60-7.50(m, 4H), 7.42 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.7 Hz, 2H), 5.53 (d, J=6.4Hz, 1H), 4.12 (q, J=5.5 Hz, 2H), 2.76-2.62 (m, 2H), 2.28 (s, 3H),1.22-1.10 (m, 1H), 0.60-0.49 (m, 2H), 0.30 (q, J=3.2, 1.6 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO d₆) δ −60.78; MS (ES+) 534.4 (M+1); 532.3 (M−1);Analysis calculated for C₃₀H₃₀F₃N₅O.2.75HCl.3H₂O: C, 52.38; H, 5.68; Cl,14.17; N, 10.18: Found: C, 52.64; H, 5.74; Cl, 13.95; N, 9.83.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123g)Step-1: Preparation of (3-aminophenyl)(4-(benzyloxy)phenyl)methanol(123b)

To a stirred solution of 4-(benzyloxy)benzaldehyde (123a) (2.122 g, 10mmol) in tetrahydrofuran (10 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding hydrogen chloride (25.00 mL, 25.00mmol), stirred for 6 h. The reaction was neutralized with 2 N NaOH (15mL) and extracted with ethyl acetate (2×50 mL). The organic layers werecombined washed with brine (50 mL), dried over anhydrous MgSO₄,filtered, and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%) to furnish(3-aminophenyl)(4-(benzyloxy)phenyl)methanol (123b) (2.691, 88% yield)as a thick yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.45-7.28 (m, 5H),7.28-7.17 (m, 2H), 6.90 (dd, J=8.2, 7.1 Hz, 3H), 6.55 (t, J=1.9 Hz, 1H),6.48 (dt, J=7.6, 1.3 Hz, 1H), 6.37 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.58(d, J=3.8 Hz, 1H), 5.45 (d, J=3.9 Hz, 1H), 5.06 (s, 2H), 4.97 (s, 2H).

Step-2: Preparation ofN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.73 g, 9.69 mmol) in DMF (10 mL) was added(3-aminophenyl)(4-(benzyloxy)phenyl)methanol (123b) (2.691 g, 8.81mmol), N-ethyl-N-isopropylpropan-2-amine (7.67 mL, 44.1 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 4.93 g,10.57 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 37 h under nitrogen atmosphere. The reaction wasdiluted with water (25 mL) and extracted with ethyl acetate (2×100 mL).The organic layers were combined, washed with brine (50 mL), dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, elutingwith 0-100% ethyl acetate in hexanes) to furnishN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123c) (2.309 g, 4.06 mmol, 46.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.19-8.12 (m, 1H), 8.00 (dt, J=7.7, 1.3Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78-7.69 (m, 2H), 7.61 (d,J=2.0 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44-7.21 (m, 9H), 7.11 (d, J=7.6Hz, 1H), 6.98-6.89 (m, 2H), 5.84 (d, J=3.8 Hz, 1H), 5.61 (d, J=3.9 Hz,1H), 5.06 (s, 2H); MS (ES+) 591.3 (M+Na); (ES−) 567.3 (M−1).

Step-3: Preparation ofN-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123d)

To a solution ofN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123c) (2.309 g, 4.06 mmol) in dichloromethane (50 mL) at 0° C. wasadded thionyl chloride (0.89 mL, 12.18 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (1.057 mL, 12.18 mmol)) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(10 mL) and added cyclopropylmethanamine (7.04 mL, 81 mmol). Thereaction mixture was heated at reflux for 48 h cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (50 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-100%ethyl acetate in hexane) to afford 1.N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123d) (0.683 g, 1.099 mmol, 27.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.69 (m, 2H), 7.64(t, J=1.7 Hz, 1H), 7.58-7.51 (m, 1H), 7.44-7.26 (m, 8H), 7.23 (d, J=7.8Hz, 1H), 7.17 (dt, J=7.7, 1.4 Hz, 1H), 6.95-6.89 (m, 2H), 5.04 (s, 2H),4.77 (s, 1H), 2.27 (d, J=6.7 Hz, 2H), 0.92 (dt, J=12.8, 4.7 Hz, 1H),0.44-0.31 (m, 2H), 0.04 (td, J=5.1, 3.4 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.96; MS (ES+) 622.4 (M+1); (ES−) 620.9 (M−1), 656.3(M+Cl). 2.N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(cyclopropylmethylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123e) (0.6 g, 0.865 mmol, 21.30% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.77 (t, J=5.6 Hz, 1H), 8.05-7.95 (m,2H), 7.68-7.57 (m, 4H), 7.54-7.48 (m, 1H), 7.44-7.25 (m, 7H), 7.22 (d,J=7.8 Hz, 1H), 7.16 (dt, J=7.7, 1.4 Hz, 1H), 6.95-6.89 (m, 2H), 5.04 (s,2H), 4.76 (s, 1H), 3.15 (dd, J=6.9, 5.5 Hz, 2H), 2.27 (d, J=6.7 Hz, 2H),1.02 (tdd, J=8.2, 6.0, 3.2 Hz, 1H), 0.96-0.81 (m, 1H), 0.48-0.30 (m,4H), 0.27-0.16 (m, 2H), 0.09-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.79; MS (ES+) 694.4 (M+1); (ES−) 692.2 (M−1); Analysis calculated forC₄₀H₃₈F₃N₅O₃.0.5H₂O: C, 68.36; H, 5.59; F, 8.11; N, 9.97; Found: C,68.37; H, 5.55; F, 7.64; N, 9.87.

Step-4 Preparation of tert-Butyl3-(5-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino) methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(123f)

To a solution ofN-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123d) (0.68 g, 1.094 mmol) in MeOH (20 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (0.716g, 3.28 mmol) and nickel(II)chloride (0.286 g, 1.203 mmol). Sodium Borohydride (0.317 g, 8.20 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.358 mL, 3.28 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(123f) (0.304 g, 0.419 mmol, 38.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.68 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7.57 (s, 1H),7.52 (d, J=7.6 Hz, 1H), 7.45-7.38 (m, 4H), 7.38-7.32 (m, 4H), 7.32-7.26(m, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.19-7.14 (m, 1H), 6.98-6.88 (m, 2H),5.04 (s, 2H), 4.76 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.27 (d, J=6.5 Hz,3H), 1.00-0.83 (m, 1H), 0.42-0.33 (m, 2H), 0.09-0.01 (m, 2H); ¹⁹F NMR(282 MHz, DMSO) δ −60.79; MS (ES+) 726.4 (M+1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123g)

To a solution of tert-butyl3-(5-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(123f) (0.32 g, 0.441 mmol) in methanol (10 mL) was added hydrogenchloride (0.919 mL, 11.02 mmol) and stirred at room temperatureovernight. The reaction mixture was concentrated in vacuum to drynessand was purified by flash column chromatography (silica gel 12 g,eluting with 0-50% methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123g) (0.228 g, 0.364 mmol, 83% yield) as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.64 (dd, J=4.2, 2.3 Hz, 3H),7.56-7.46 (m, 3H), 7.45-7.14 (m, 10H), 6.95-6.89 (m, 2H), 5.05 (s, 2H),4.76 (s, 1H), 3.98 (s, 2H), 2.27 (d, J=6.7 Hz, 2H), 0.98-0.82 (m, 1H),0.43-0.32 (m, 2H), 0.04 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.76; MS(ES+) 626.4 (M+1); (ES−) 660.3 (M−1); Analysis calculated forC₃₆H₃₄F₃N₅O₂.2H₂O: C, 65.34; H, 5.79; N, 10.58; Found: C, 65.39; H,5.55; N, 10.50.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124f) Step-1: Preparation of(3-Aminophenyl)(3-(trifluoromethoxy)phenyl)methanol (124b)

To a stirred solution of 3-(trifluoromethoxy)benzaldehyde (124a) (1.9 g,10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding hydrogen chloride (25.00 mL, 25.00mmol), stirred for 6 h. The reaction was neutralized with 2 N NaOH (15mL) and extracted with ethyl acetate (2×50 mL). The organic layers werecombined washed with brine (50 mL), dried over anhydrous MgSO₄,filtered, and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%) to furnish(3-Aminophenyl)(3-(trifluoromethoxy)phenyl)methanol (124b) (1.5 g, 53%yield) as a thick yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.47-7.29 (m,3H), 7.18 (ddt, J=7.9, 2.5, 1.2 Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.58(t, J=2.0 Hz, 1H), 6.51 (dt, J=7.6, 1.3 Hz, 1H), 6.40 (ddd, J=8.0, 2.3,1.1 Hz, 1H), 5.91 (d, J=3.9 Hz, 1H), 5.57 (d, J=3.9 Hz, 1H), 5.05 (s,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −56.58; MS (ES+) 284.2 (M+1), 306.2(M+Na); (ES−) 282.1 (M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.495 g, 5.32 mmol) in DMF (20 mL) was(3-aminophenyl)(3-(trifluoromethoxy)phenyl)methanol (124b) (1.369 g,4.83 mmol), N-ethyl-N-isopropylpropan-2-amine (4.21 mL, 24.17 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 2.70 g,5.80 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (75 mL) and extracted with ethyl acetate (2×75 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and evaporated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124c) (2.081 g, 3.81 mmol, 79% yield) as a yellow semisolid; 1H NMR(300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt,J=7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77-7.70 (m,2H), 7.67 (t, J=1.8 Hz, 1H), 7.58 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.44(t, J=8.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.23-7.13(m, 2H), 6.18 (d, J=3.9 Hz, 1H), 5.76 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −56.62, −60.98; MS (ES+) 569.2 (M+Na); (ES−) 545.2(M−1).

Step-3: Preparation of tert-Butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(124d)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124c) (0.44 g, 0.734 mmol) in MeOH (10 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (0.481 g, 2.202 mmol) and nickel(II)chloride (0.192 g, 0.807 mmol). Sodium Borohydride (0.212 g, 5.50 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.240 mL, 2.202 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdissolved in dichloromethane (60 mL) and water (60 mL). The aqueousphase was separated and extracted again with dichloromethane (60 mL).The organic extracts were combined, washed with brine (60 mL), driedover MgSO₄, filtered and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 24 gwith 0-100% 9:1 ethyl acetate/methanol in hexane) to afford tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(124d) (0.304 g, 0.432 mmol, 58.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.57 (s, 1H),7.57-7.38 (m, 6H), 7.37-7.35 (m, 1H), 7.33 (s, 1H), 7.29-7.17 (m, 3H),4.89 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.59-2.54 (m, 1H), 2.39-2.16 (m,2H), 1.35 (s, 9H), 0.99-0.83 (m, 1H), 0.43-0.30 (m, 2H), 0.09-−0.01 (m,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −56.60, −60.80; MS (ES+) 704.4 (M+1),727.5 (M+Na), (ES−) 703.3 (M−1).

Step-4: Preparation of1-(3-Cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124e)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124d) (0.769 g, 1.407 mmol) in dichloromethane (25 mL) at 0° C. wasadded thionyl chloride (0.308 mL, 4.22 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withcyclopropylmethanamine (0.366 mL, 4.22 mmol) and stirred at roomtemperature for additional 5 h. The reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile (5mL) and added cyclopropylmethanamine (2.441 mL, 28.1 mmol). The reactionmixture was heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (50 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 24 g, eluting 0-100% ethyl acetate inhexane) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124e) (0.449 g, 0.749 mmol, 53.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.79-7.66 (m, 3H),7.60-7.47 (m, 1H), 7.46-7.37 (m, 3H), 7.32-7.14 (m, 3H), 4.90 (s, 1H),2.38-2.15 (m, 3H), 1.00-0.80 (m, 1H), 0.44-0.32 (m, 2H), 0.08-0.01 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −56.60, −60.96; MS (ES+) 600.3 (M+1);(ES−) 634.1 (M+Cl).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124f)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (124e) (0.194 g, 0.276 mmol) in methanol (10 mL) wasadded hydrogen chloride (0.574 mL, 6.89 mmol), stirred at roomtemperature overnight and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 12 g,eluting with 0-50% methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(124f) (0.05 g, 0.083 mmol, 30.0% yield) as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.49 (s, 3H), 7.79-7.68 (m, 3H),7.66-7.44 (m, 6H), 7.29 (dd, J=25.9, 7.6 Hz, 3H), 5.13 (s, 1H), 4.12 (s,2H), 2.46-2.34 (m, 2H), 0.98 (d, J=8.9 Hz, 1H), 0.43 (d, J=7.6 Hz, 2H),0.26-0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −56.61, −60.79; MS (ES+)604.3 (M+1); (ES−) 602.3 (M−1); Analysis calculated forC₃₀H₂₇F₆N₅O₂.1.25HCl.0.5H₂O: C, 54.75; H, 4.48; Cl, 6.73; N, 10.64;Found: C, 54.61; H, 4.51; Cl, 6.81; N, 10.50.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenanthren-9-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(125g) Step-1: Preparation of (3-Amino-phenyl)-phenanthren-9-yl-methanol(125b)

To a stirred solution of Phenanthrene-9-carbaldehyde (125a) (1.2 g, 10mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was neutralized with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish (3-Amino-phenyl)-phenanthren-9-yl-methanol(125b) (2.5 g, 83.5%) as a light brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.82 (ddd, J=9.3, 7.3, 2.3 Hz, 2H), 8.16-8.07 (m, 1H),8.06-7.97 (m, 2H), 7.74-7.58 (m, 3H), 7.52 (ddd, J=8.2, 6.9, 1.3 Hz,1H), 6.94 (t, J=7.7 Hz, 1H), 6.63 (d, J=7.5 Hz, 1H), 6.54 (t, J=1.9 Hz,1H), 6.39 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 6.19 (d, J=4.4 Hz, 1H), 5.97(d, J=4.4 Hz, 1H), 4.95 (s, 2H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenanthren-9-yl-methyl)-phenyl]-amide (125c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.348 g, 8.35 mmol) in DMF (45 mL) was added(3-Amino-phenyl)-phenanthren-9-yl-methanol (125b) (2.5 g, 8.35 mmol),N-ethyl-N-isopropylpropan-2-amine (11.0 mL, 66.8 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 3.89 g,8.350 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 21 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (350 mL) washed with water (2×150 mL), brine(120 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-30%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenanthren-9-yl-methyl)-phenyl]-amide (125c) (2.1 g, 44.77%yield) as a red brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.59(s, 1H), 8.92-8.76 (m, 2H), 8.15-8.00 (m, 4H), 7.98 (dt, J=7.7, 1.3 Hz,1H), 7.86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73-7.59 (m, 6H), 7.56 (s,1H), 7.51 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.32-7.25 (m, 2H), 6.34 (d,J=4.3 Hz, 1H), 6.25 (d, J=4.3 Hz, 1H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenyl}-amide(125d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenanthren-9-yl-methyl)-phenyl]-amide (125c) (2.0 g, 3.56mmol) in dichloromethane (40 mL) at 0° C. was added thionyl chloride(0.85 g, 7.11 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (3.79 g, 53.33 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue obtained was dissolved indichloromethane (40 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-40% ethyl acetate inhexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenyl}-amide(125d) (1.22 g, 55.66%) as pale solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.51(s, 1H), 8.81-8.74 (m, 1H), 8.74-8.68 (m, 1H), 8.22-8.16 (m, 1H), 8.06(s, 1H), 8.04 (t, J=1.9 Hz, 1H), 7.90 (ddt, J=7.7, 6.7, 1.6 Hz, 2H),7.77 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.61-7.58 (m, 2H), 7.57-7.54 (m,3H), 7.51 (dt, J=6.7, 1.4 Hz, 3H), 7.28 (dt, J=7.6, 1.4 Hz, 1H),7.24-7.16 (m, 1H), 5.54 (s, 1H), 2.38 (d, J=6.8 Hz, 3H), 1.01-0.87 (m,1H), 0.42-0.26 (m, 2H), 0.09-−0.08 (m, 2H).

Step-4: Preparation of[3-(5-{3-[(Cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (125e) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-phenanthren-9-yl-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (125f)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenyl}-amide(125d) (1.2 g, 1.95 mmol) in MeOH (24 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.556 g, 2.338 mmol) and Bocanhydride (1.3 mL, 5.847 mmol) followed by portionwise addition ofsodium borohydride (0.44 g, 11.694 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (0.5 mL, 4.872 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish

-   -   1.        [3-(5-{3-[(Cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamic        acid tert-butyl ester (125e) (0.3 g, 18.79%) as a white solid;        ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.91 (d, J=8.1 Hz,        1H), 8.84 (d, J=8.3 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.88 (d,        J=7.6 Hz, 1H), 7.75-7.66 (m, 4H), 7.63 (d, J=8.3 Hz, 2H), 7.49        (d, J=15.4 Hz, 4H), 7.50-7.43 (m, 3H), 7.40-7.32 (m, 4H), 7.30        (t, J=1.9 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 4.16 (d, J=6.3 Hz,        2H), 3.19 (dt, J=27.1, 7.8 Hz, 2H), 1.36 (s, 18H), 0.86-0.70 (m,        1H), 0.01-−0.06 (m, 2H), −0.15-−0.33 (m, 2H).    -   2.        [(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-phenanthren-9-yl-methyl]-cyclopropylmethyl-carbamic        acid tert-butyl ester (125f) (0.62 g, 38.82%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.80-8.74 (m, 1H), 8.74-8.65(m, 1H), 8.25-8.15 (m, 1H), 8.06 (s, 1H), 7.91 (dt, J=6.3, 2.6 Hz, 1H),7.60-7.55 (m, 2H), 7.54-7.48 (m, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.34-7.15(m, 7H), 5.53 (s, 1H), 4.08 (d, J=6.3 Hz, 2H), 2.36 (s, 2H), 1.25 (s,9H), 1.00-0.86 (m, 1H), 0.40-0.25 (m, 2H), −0.01 (dd, J=9.1, 4.7 Hz,2H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenyl}-amide(125g)

To a solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (125e) (0.250 g, 0.35 mmol) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-phenanthren-9-yl-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (125f) (0.5 g, 0.695 mmol) were dissolvedseparately in methanol (10 mL) and added conc. HCL (0.5 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. NMR of the residue in methanol and TLC shows samecompound. The products were combined dried and purified by flash columnchromatography (silica gel 12 g, eluting with 0-15% methanol indichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenanthren-9-yl-methyl]-phenyl}-amide(125g) (0.3 g, 46%) free base as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.90 (s, 1H), 10.09 (s, 1H), 8.98-8.90 (m, 1H), 8.89-8.83(m, 1H), 8.54 (s, 1H), 8.42 (s, 3H), 8.24-8.15 (m, 1H), 8.07-7.99 (m,1H), 7.87 (s, 1H), 7.81-7.57 (m, 10H), 7.46 (ddt, J=17.2, 15.4, 7.8 Hz,3H), 6.43 (s, 1H), 4.10 (s, 2H), 3.12-2.74 (m, 2H), 1.31-1.13 (m, 1H),0.57 (d, J=7.8 Hz, 2H), 0.31 (d, J=26.4 Hz, 2H); ¹H NMR (300 MHz,DMSO-d₆/D₂O) δ 8.96-8.90 (m, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.41 (s, 1H),8.18 (dd, J=8.4, 1.5 Hz, 1H), 8.09-8.03 (m, 1H), 7.86-7.55 (m, 12H),7.54-7.42 (m, 3H), 6.41 (s, 1H), 4.10 (s, 2H), 3.13-2.76 (m, 2H),1.26-1.16 (m, 1H), 0.59 (d, J=8.0 Hz, 2H), 0.31 (d, J=25.2 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.81; MS (ES+) 620.4 (M+1); (ES−) 654.3(M+Cl). Free base of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenanthren-9-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(125g) (250 mg) from above was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% methanol in chloroform) andconverted to hydrochloride by dissolving the product obtained inmethanol (5 mL) and treating it with 10 equivalents of conc. HCl. Thesolution obtained was concentrated in vacuum to dryness dried in vacuumto furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(125 g) (70 mg, 99%) hydrochloride salt as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.39 (d, J=10.4 Hz, 1H), 10.19 (s,1H), 8.93 (dd, J=8.4, 1.5 Hz, 1H), 8.90-8.81 (m, 1H), 8.66 (s, 1H), 8.53(s, 3H), 8.21 (dd, J=8.3, 1.5 Hz, 1H), 8.08-8.00 (m, 1H), 7.96-7.90 (m,1H), 7.80-7.61 (m, 9H), 7.56-7.37 (m, 3H), 6.46 (t, J=6.2 Hz, 1H), 4.10(q, J=6.0 Hz, 2H), 3.11-2.98 (m, 1H), 2.84 (td, J=9.5, 8.9, 4.2 Hz, 1H),1.26 (ddd, J=12.6, 6.2, 3.6 Hz, 1H), 0.57 (dd, J=8.2, 4.0 Hz, 2H),0.43-0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80; MS (ES+) 620.4(M+1); (ES−) 618.4 (M−1); Analysis calculated for C₃₇H₃₂F₃N₅O.2HCl.2H₂O:C, 60.99; H, 5.26; Cl, 9.73; N, 9.61; Found: C, 60.82; H, 5.24; Cl,9.92; N, 9.66.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(dimethylamino)naphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(126g) Step-1: Preparation of(3-Amino-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methanol (126b)

To a stirred solution of 4-Dimethylamino-naphthalene-1-carbaldehyde(126a) (1.2 g, 10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (12.5 mL). The reactionmixture was stirred for 6 h and basified with 2 N NaOH (15 mL) andextracted with ethyl acetate (2×50 mL). The organic layers were combinedwashed with saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered and evaporated to dryness. The crude residue was purified byflash column chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to(3-Amino-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methanol (126b) (1.9g, 65%) as a light brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.17-8.11 (m,1H), 8.11-8.06 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.40 (dqd, J=10.0, 6.7,1.5 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 6.94-6.84 (m, 1H), 6.57-6.49 (m,2H), 6.40-6.32 (m, 1H), 6.08 (d, J=4.4 Hz, 1H), 5.73 (t, J=2.2 Hz, 1H),4.93 (s, 2H), 2.78 (s, 6H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid{3-[(4-dimethylamino-naphthalen-1-yl)-hydroxy-methyl]-phenyl}-amide(126c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.9 g, 6.756 mmol) in DMF (22 mL) was added(3-Amino-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methanol (126b) (1.9g 6.756 mmol), N-ethyl-N-isopropylpropan-2-amine (6.98 g, 54.048 mmol)and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 3.065g, 6.756 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 39 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (200 mL) washed with water (2×300 mL), brine(200 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-25%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(4-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide (126c)(0.7 g,) as a light brown liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s,1H), 8.16-8.09 (m, 2H), 8.09-8.04 (m, 1H), 7.95 (dt, J=7.7, 1.3 Hz, 1H),7.85 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.65 (s,1H), 7.58 (d, J=2.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.47 (d, J=7.8 Hz, 1H),7.39 (dddd, J=17.3, 8.2, 6.8, 1.5 Hz, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.13(d, J=7.7 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.21 (d, J=4.3 Hz, 1H), 5.97(d, J=4.2 Hz, 1H), 2.77 (s, 6H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(4-dimethylamino-naphthalen-1-yl)-hydroxy-methyl]-phenyl}-amide(126c) (0.7 g, 1.260 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.299 g, 2.520 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (30 mL) and addedcyclopropylmethanamine (1.34 g, 18.9 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-100% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126d) (0.4 g) as a brown sticky liquid; ¹HNMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H), 8.18 (dd, J=6.7, 3.2 Hz, 1H), 8.14-8.08 (m, 1H), 8.07 (t,J=1.9 Hz, 1H), 7.92 (dt, J=7.7, 1.3 Hz, 1H), 7.81 (ddd, J=8.3, 2.2, 1.2Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.59-7.52 (m,2H), 7.52-7.45 (m, 1H), 7.44-7.35 (m, 2H), 7.24-7.14 (m, 2H), 7.06 (d,J=7.9 Hz, 1H), 5.47 (s, 1H), 2.72 (s, 6H), 2.32 (d, J=6.6 Hz, 2H),1.00-0.82 (m, 1H), 0.32 (dd, J=7.7, 1.3 Hz, 2H), 0.07-−0.08 (m, 2H).

Step-4: Preparation of[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicAcid tert-butyl ester (126f) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methyl]-cyclopropylmethyl-carbamicAcid tert-butyl ester (126e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126d) (0.4 g, 0.656 mmol) in MeOH (10 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.195 g, 0.821 mmol) and Bocanhydride (0.429 g, 1.968 mmol) followed by portionwise addition ofSodium Borohydride (0.148 g, 3.936 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (0.270 mL, 2.624 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% chloroform/methanol) to furnish[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (126f) (0.170 g, 32%) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.25 (dt, J=7.8, 2.7 Hz, 1H),8.05-7.93 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.61-7.48 (m, 5H), 7.44 (dd,J=7.0, 2.1 Hz, 2H), 7.40-7.34 (m, 3H), 7.07 (d, J=7.9 Hz, 1H), 6.97 (t,J=8.7 Hz, 2H), 4.21 (d, J=6.2 Hz, 2H), 3.36-3.23 (m, 2H), 2.84 (s, 6H),1.48-1.35 (bs, 18H), 0.34 (m, 1H), −0.00 (m, 1H), −0.27 (m, 2H), −0.87(m, 1H)} and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (126e) (0.140 g, 30%) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.31-8.05 (m, 2H), 7.66-7.13 (m,12H), 7.07 (d, J=7.9 Hz, 1H), 6.93 (dt, J=35.7, 8.2 Hz, 1H), 5.47 (s,1H), 4.12 (d, J=6.2 Hz, 2H), 2.73 (s, 6H), 2.33 (d, J=6.8 Hz, 2H), 1.29(s, 9H), 1.00-0.84 (m, 1H), 0.40-0.27 (m, 2H), 0.05-−0.07 (m, 3H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126g)

A solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (126f) (0.160 g, 0.197 mmol) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-(4-dimethylamino-naphthalen-1-yl)-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (126e) (0.13 g, 0.182 mmol) were dissolvedseparately in methanol (2.5 mL) and added conc. HCl (0.5 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. NMR of the residue in methanol and TLC shows samecompound. The products were combined dried and purified by flash columnchromatography (silica gel 12 g, eluting with 0-150% methanol indichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126g) (0.135 g, 28%) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.06 (d, J=4.5 Hz, 1H), 10.46 (s, 1H), 10.17 (s, 1H), 8.68 (s, 3H),8.26 (q, J=4.9 Hz, 2H), 7.94 (s, 1H), 7.75-7.64 (m, 5H), 7.63-7.35 (m,6H), 6.50-6.25 (m, 1H), 4.10 (q, J=5.8 Hz, 2H), 2.93 (s, 8H), 1.25 (d,J=7.5 Hz, 1H), 0.62-0.48 (m, 2H), 0.30 (qd, J=9.4, 4.2 Hz, 2H); 1H NMR(300 MHz, DMSO-d₆) δ 8.37-8.30 (m, 1H), 8.28-8.21 (m, 1H), 8.18 (d,J=8.0 Hz, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.73-7.38 (m, 12H), 6.38 (s, 1H),4.11 (s, 2H), 3.00-2.76 (m, 8H), 1.24-1.14 (m, 1H), 0.56 (d, J=8.2 Hz,2H), 0.42-0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+)613.3 (M+1), 635.3 (M+Na); (ES−) 647.3 (M+Cl); Analysis calculated forC₃₅H₃₅F₃N₆O.3HCl.12H₂O.6.5NaCl: C, 31.89; H, 4.74; Cl, 25.55; N, 6.38Found: C, 32.28; H, 4.39; Cl, 25.46; N, 6.10.2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126g) (170 mg) from above was purified by flash column chromatography(silica gel 12 g, eluting with 0-25% methanol in chloroform) andconverted to hydrochloride salt by dissolving the product obtained inmethanol (5 mL) and treating it with 10 equivalents of conc HCl. Thesolution obtained was concentrated in vacuum to dryness dried in vacuumto furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-dimethylamino-naphthalen-1-yl)-methyl]-phenyl}-amide(126g) (70 mg, 99%) hydrochloride salt as a pale yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 10.98 (d, J=1.6 Hz, 1H), 10.34 (s, 1H), 10.08 (s,1H), 8.54 (s, 2H), 8.38 (s, 1H), 8.31-8.17 (m, 2H), 7.94-7.84 (m, 1H),7.72 (d, J=1.9 Hz, 1H), 7.70-7.57 (m, 6H), 7.54 (d, J=7.8 Hz, 1H),7.53-7.46 (m, 1H), 7.41 (td, J=7.9, 1.3 Hz, 1H), 6.39 (t, J=6.3 Hz, 1H),4.97 (d, J=5.4 Hz, 1H), 4.11 (q, J=5.9 Hz, 2H), 2.97 (s, 6H), 2.43 (d,J=14.0 Hz, 2H), 1.31-1.17 (m, 1H), 0.65-0.47 (m, 2H), 0.41-0.19 (m, 2H);¹⁹F NMR (282 MHz, DMSO) δ −60.78; MS (ES−) 647.3 (M+Cl); Analysiscalculated for C₃₅H₃₅F₃N₆O.2.75HCl.3H₂O: C, 54.81; H, 5.75; Cl, 12.71;N, 10.96: Found: C, 55.22; H, 5.78; Cl, 12.77; N, 10.28.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-propoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(127f) Step-1: Preparation of(3-Amino-phenyl)-(4-propoxy-phenyl)-methanol (127b)

To a stirred solution of 4-Propoxy-benzaldehyde (127a) (1.2 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to afford (3-Amino-phenyl)-(4-propoxy-phenyl)-methanol (127b)(2.0 g, 77.72%) as a light brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.24-7.18 (m, 2H), 6.90 (t, J=7.7 Hz, 1H), 6.85-6.80 (m, 2H),6.55 (t, J=1.9 Hz, 1H), 6.48 (dt, J=7.7, 1.3 Hz, 1H), 6.37 (ddd, J=7.9,2.4, 1.0 Hz, 1H), 5.57 (d, J=3.9 Hz, 1H), 5.44 (d, J=3.9 Hz, 1H), 4.97(s, 2H), 3.86 (td, J=6.6, 3.3 Hz, 2H), 1.77-1.59 (m, 2H), 0.95 (t, J=7.4Hz, 3H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(4-propoxy-phenyl)-methyl]-phenyl}-amide (127c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.16 g, 7.69 mmol) in DMF (40 mL) was added(3-Amino-phenyl)-(4-propoxy-phenyl)-methanol (127b) (1.80 g, 6.99 mmol),N-ethyl-N-isopropylpropan-2-amine (9.8 mL, 55.96 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 3.59 g,7.69 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 19 h under nitrogen atmosphere. The reaction was dilutedwith ethyl acetate (50 mL) washed with water (2×50 mL), brine (50 mL),dried, filtered, and evaporated to dryness. The residue obtained waspurified by flash column chromatography [silica gel 120 g, eluting withethyl acetate in hexanes from 0-25%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(4-propoxy-phenyl)-methyl]-phenyl}-amide (127c) (2.0 g, 55%)as a light brown liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.21(t, J=1.9 Hz, 1H), 8.06 (dt, J=7.8, 1.3 Hz, 1H), 7.96 (ddd, J=8.2, 2.2,1.1 Hz, 1H), 7.84-7.73 (m, 2H), 7.67 (t, J=1.8 Hz, 1H), 7.64-7.54 (m,1H), 7.31 (s, 1H), 7.31-7.24 (m, 2H), 7.17 (d, J=7.8 Hz, 1H), 6.95-6.85(m, 2H), 5.89 (d, J=3.9 Hz, 1H), 5.67 (d, J=3.9 Hz, 1H), 3.93 (t, J=6.5Hz, 2H), 1.75 (h, J=7.1 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenyl}-amide(127d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(4-propoxy-phenyl)-methyl]-phenyl}-amide (127c) (2.0 g, 3.84mmol) in dichloromethane (40 mL) at 0° C. was added thionyl chloride(0.914 g, 7.68 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (5.0 g, 57.636 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-50% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenyl}-amide(127d) (1.14 g, 51.76%) as a pale sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.59 (s, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.8, 1.3Hz, 1H), 7.86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H),7.67 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.53-7.45 (m, 1H), 7.26-7.16 (m,3H), 7.16-7.09 (m, 1H), 6.82-6.75 (m, 2H), 4.72 (s, 1H), 3.81 (t, J=6.5Hz, 2H), 2.23 (d, J=6.6 Hz, 2H), 1.74-1.53 (m, 2H), 0.90 (t, J=7.4 Hz,3H), 0.87-0.74 (m, 1H), 0.39-0.28 (m, 2H), 0.00 (m, 2H).

Step-4: Preparation of[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicAcid Tert-Butyl Ester (127e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenyl}-amide(127d) (1.0 g, 1.74 mmol) in MeOH (24 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.49 g, 2.09 mmol) and Bocanhydride (1.2 mL, 5.23 mmol) followed by portion-wise addition ofsodium borohydride (0.395 g, 10.46 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (0.5 mL, 4.36 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-40% Ethyl acetate/n-hexane) to furnish[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (127e) (0.5 g, 42.40%) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.64-7.55 (m, 1H), 7.52 (s, 1H),7.50-7.42 (m, 2H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, 2H), 7.26-7.17 (m,3H), 7.17-7.09 (m, 1H), 6.82-6.74 (m, 2H), 4.71 (s, 1H), 4.15 (d, J=6.2Hz, 2H), 3.81 (t, J=6.5 Hz, 2H), 2.23 (d, J=6.7 Hz, 2H), 1.64 (q, J=6.9Hz, 2H), 1.31 (s, 9H), 0.90 (t, J=7.4 Hz, 3H), 0.85-0.74 (m, 1H),0.39-0.27 (m, 2H), 0.00 (dd, J=5.5, 3.8 Hz, 2H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenyl}-amide(127f)

A solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (127e) (0.500 g, 0.74 mmol) was dissolved inmethanol (10 mL) and added conc. HCl (0.5 mL). The reaction mixture wasstirred at room temperature overnight and concentrated in vacuum todryness. The residue was azeotroped with toluene (2×10 mL) and ethanol(10 mL), dried in vacuum pump to furnish a white solid residue. Theproduct was purified by flash column chromatography (silica gel 12 g,eluting with 0-15% methanol in dichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(4-propoxy-phenyl)-methyl]-phenyl}-amide(127f) (120 mg, 20.87%) as a pale white powder; ¹H NMR (300 MHz,DMSO-d₆) δ 10.96 (s, 1H), 9.96 (s, 2H), 8.47 (s, 3H), 7.83 (s, 1H), 7.73(s, 1H), 7.70 (s, 1H), 7.58 (dtt, J=17.6, 6.3, 3.9 Hz, 7H), 7.43 (t,J=7.8 Hz, 1H), 6.96 (d, J=8.2 Hz, 2H), 5.64-5.37 (m, 1H), 4.12 (q,J=5.7, 5.3 Hz, 2H), 3.91 (t, J=6.4 Hz, 2H), 2.68 (q, J=9.4, 6.4 Hz, 2H),1.70 (q, J=6.9 Hz, 2H), 1.20-1.05 (m, 1H), 0.95 (t, J=7.3 Hz, 3H),0.60-0.48 (m, 2H), 0.30 (t, J=4.7 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.64-7.41 (m,8H), 6.98 (d, J=8.3 Hz, 2H), 5.52 (s, 1H), 4.13 (s, 2H), 3.92 (t, J=6.4Hz, 2H), 2.70 (dd, J=7.1, 3.4 Hz, 2H), 1.70 (q, J=6.9 Hz, 2H), 1.09 (q,J=6.8, 6.1 Hz, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.64-0.50 (m, 2H), 0.29 (d,J=4.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS (ES+) 578.4(M+1); (ES−) 612.4 (M+Cl); Analysis calculated forC₃₂H₃₄F₃N₅O₂.2.75HCl.5.5H₂O: C, 49.47; H, 6.19; Cl, 12.55; N, 9.01;Found: C, 49.44; H, 5.81; Cl, 12.47; N, 8.83.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalen-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(128g) Step-1: Preparation of (3-Amino-phenyl)-naphthalen-2-yl-methanol(128b)

To a stirred solution of naphthalene-2-carbaldehyde (128a) (1.2 g, 10mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-Amino-phenyl)-naphthalen-2-yl-methanol (128b) (2.4g, 96.27%) as a light brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ7.82 (dd, J=8.1, 1.6 Hz, 3H), 7.75 (d, J=8.6 Hz, 1H), 7.45-7.36 (m, 3H),6.87 (t, J=7.7 Hz, 1H), 6.58-6.48 (m, 2H), 6.33 (ddd, J=7.9, 2.3, 1.0Hz, 1H), 5.79 (d, J=3.8 Hz, 1H), 5.62 (d, J=3.8 Hz, 1H), 4.93 (s, 2H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-naphthalen-2-yl-methyl)-phenyl]-amide (128c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.4 g, 8.54 mmol) in DMF (48 mL) was added3-Amino-phenyl)-naphthalen-2-yl-methanol (128b) (2.12 g, 8.535 mmol),N-ethyl-N-isopropylpropan-2-amine (11.8 g, 68.24 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP; 3.97 g,8.54 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 42 h under nitrogen atmosphere. The reaction was dilutedwith ethyl acetate (350 mL) washed with water (2×150 mL), brine (120mL), dried, filtered, and evaporated to dryness. The residue obtainedwas purified by flash column chromatography [silica gel 120 g, elutingwith ethyl acetate in hexanes from 0-30%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-naphthalen-2-yl-methyl)-phenyl]-amide (128c) (2.6 g, 59.4%yield) as a brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s,1H), 8.15 (t, J=1.9 Hz, 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.95-7.86 (m,4H), 7.83 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.66(t, J=1.8 Hz, 1H), 7.60-7.55 (m, 1H), 7.51-7.46 (m, 2H), 7.43 (dd,J=8.7, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.21 (dt, J=7.8, 1.4 Hz,1H), 6.11 (d, J=3.8 Hz, 1H), 5.85 (d, J=3.8 Hz, 1H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenyl}-amide(128d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-naphthalen-2-yl-methyl)-phenyl]-amide (128c) (2.6 g, 5.07mmol) in dichloromethane (50 mL) at 0° C. was added thionyl chloride(1.2 g, 10.14 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (5.41 g, 76.05 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenyl}-amide(128d) (0.90 g, 31.39%) as brown liquid; ¹H NMR (300 MHz, DMSO-d₆) δ10.58 (s, 1H), 8.09 (t, J=1.9 Hz, 1H), 7.92 (dt, J=7.7, 1.3 Hz, 1H),7.89-7.86 (m, 1H), 7.85-7.73 (m, 4H), 7.69-7.62 (m, 3H), 7.45 (dddd,J=19.3, 9.5, 5.3, 2.4 Hz, 4H), 7.24-7.16 (m, 2H), 4.94 (s, 1H),2.36-2.17 (m, 2H), 0.99-0.83 (m, 1H), 0.38-0.24 (m, 2H), −0.01 (m, 2H).

Step-4: Preparation of[3-(5-{3-[(Cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (128e) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-naphthalen-2-yl-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (128f)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenyl}-amide(128d) (0.90 g, 1.59 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.47 g, 1.99 mmol) and Bocanhydride (1.04 g, 4.77 mmol) followed by portionwise addition of sodiumborohydride (0.36 g, 9.55 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.7 mL, 6.36 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL).

The combined extracts were washed with brine (25 mL), dried over MgSO₄filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel 24 g, eluting with 0-25%Ethyl acetate/hexane) to furnish

-   -   1.        [3-(5-{3-[(Cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamic        acid tert-butyl ester (128e) (0.42 g, 34.31%)¹H NMR (300 MHz,        DMSO-d₆) δ 10.56 (s, 1H), 7.75 (dd, J=9.2, 3.2 Hz, 2H), 7.70 (d,        J=3.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.38-7.34 (m, 4H), 7.31        (s, 1H), 7.25-7.20 (m, 1H), 7.20-7.16 (m, 5H), 6.83 (d, J=7.8        Hz, 1H), 6.30 (s, 1H), 4.02 (d, J=6.2 Hz, 2H), 3.06-2.94 (m,        2H), 1.15 (s, 18H), 0.45 (s, 1H), 0.01 (d, J=8.6 Hz, 2H), −0.32        (s, 2H).    -   2.        [(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-naphthalen-2-yl-methyl]-cyclopropylmethyl-carbamic        acid tert-butyl ester (128f) (0.26 g, 24.42%); ¹H NMR (300 MHz,        DMSO-d₆) δ 10.62 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.81 (d, J=9.8        Hz, 2H), 7.77-7.72 (m, 2H), 7.62 (s, 1H), 7.49-7.38 (m, 6H),        7.34 (dd, J=8.9, 2.2 Hz, 2H), 7.30-7.25 (m, 2H), 7.19 (d, J=6.5        Hz, 2H), 4.93 (s, 1H), 4.12 (d, J=6.2 Hz, 2H), 2.24 (d, J=18.8        Hz, 2H), 1.29 (d, J=4.5 Hz, 9H), 0.99-0.79 (m, 1H), 0.41-0.26        (m, 2H), −0.01 (q, J=4.9 Hz, 2H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenyl}-amide(128g)

A solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (128e) (0.42 g, 0.55 mmol) and[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-naphthalen-2-yl-methyl]-cyclopropylmethyl-carbamicacid tert-butyl ester (128g) (0.26 g, 0.39 mmol) were dissolvedseparately in methanol (10 mL) and added conc. HCl (0.5 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. NMR of the residue in methanol and TLC shows samecompound. The products were combined dried and purified by flash columnchromatography (silica gel 12 g, eluting with 0-15% methanol indichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-2-yl-methyl]-phenyl}-amide(128g) (0.6 g, 95.42%) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.94(s, 1H), 10.14 (s, 2H), 8.41 (s, 3H), 8.22 (d, J=1.7 Hz, 1H), 7.98 (d,J=8.6 Hz, 1H), 7.92 (dt, J=5.8, 3.2 Hz, 3H), 7.76 (dd, J=8.6, 1.8 Hz,1H), 7.72 (d, J=1.9 Hz, 1H), 7.69-7.42 (m, 10H), 5.77 (d, J=3.4 Hz, 1H),4.12 (d, J=5.6 Hz, 3H), 2.75 (d, J=12.4 Hz, 3H), 1.18 (dd, J=8.1, 3.8Hz, 1H), 0.66-0.50 (m, 2H), 0.38-0.22 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.80; MS (ES+) 570.3 (M+1); (ES−) 604.3 (M+Cl); Analysiscalculated for C₃₃H₃₀F₃N₅O.2.05HCl.2H₂O: C, 58.25; H, 5.34; Cl, 10.68;N, 10.29; Found: C, 58.14; H, 5.58; Cl, 11.02; N, 9.90.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(129f) Step-1: Preparation of (3-Amino-phenyl)-naphthalen-1-yl-methanol(129b)

To a stirred solution of naphthalene-1-carbaldehyde (129a) (1.2 g, 10mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL,12.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-Amino-phenyl)-naphthalen-1-yl-methanol (129b)(2.45 g, 98.27%) as a light brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.16-8.06 (m, 1H), 7.93-7.86 (m, 1H), 7.82 (d, J=8.1 Hz, 1H),7.71-7.66 (m, 1H), 7.51 (dd, J=8.2, 7.1 Hz, 1H), 7.48-7.39 (m, 2H), 6.91(t, J=7.9 Hz, 1H), 6.63-6.49 (m, 2H), 6.38 (ddd, J=7.9, 2.2, 1.1 Hz,1H), 6.19 (d, J=4.4 Hz, 1H), 5.85 (d, J=4.4 Hz, 1H), 4.96 (s, 2H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid[3-(hydroxy-naphthalen-1-yl-methyl)-phenyl]-amide (129c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.47 g, 8.8 mmol) in DMF (40 mL) was added(3-Amino-phenyl)-naphthalen-1-yl-methanol (129b) (2.0 g, 8.8 mmol),N-ethyl-N-isopropylpropan-2-amine (12.26 mL, 70.42 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 4.1 g,8.8 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 42 h under nitrogen atmosphere. The reaction was dilutedwith ethyl acetate (350 mL) washed with water (2×150 mL), brine (120mL), dried, filtered, and evaporated to dryness. The residue obtainedwas purified by flash column chromatography [silica gel 120 g, elutingwith ethyl acetate in hexanes from 0-30%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid[3-(hydroxy-naphthalen-1-yl-methyl)-phenyl]-amide (129c) (1.0 g, 22.17%)as a brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H),8.17-8.08 (m, 2H), 7.99 (dt, J=7.8, 1.3 Hz, 1H), 7.94-7.82 (m, 3H), 7.73(d, J=7.9 Hz, 1H), 7.70-7.50 (m, 5H), 7.50-7.39 (m, 2H), 7.26 (t, J=7.8Hz, 1H), 7.21-7.12 (m, 1H), 6.34 (d, J=4.3 Hz, 1H), 6.13 (d, J=4.3 Hz,1H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenyl}-amide(129d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid[3-(hydroxy-naphthalen-1-yl-methyl)-phenyl]-amide (129c) (1.0 g, 1.95mmol) in dichloromethane (50 mL) at 0° C. was added thionyl chloride(0.28 mL, 3.902 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (2.053 g, 29.265 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenyl}-amide(129d) (0.60 g, 54.40%) as brown liquid; ¹H NMR (300 MHz, DMSO-d₆) δ10.57 (s, 1H), 8.29-8.17 (m, 1H), 8.12-8.06 (m, 1H), 7.94 (dt, J=7.8,1.3 Hz, 1H), 7.89-7.81 (m, 2H), 7.78-7.56 (m, 5H), 7.55-7.40 (m, 4H),7.27-7.17 (m, 2H), 5.58 (s, 1H), 2.35 (d, J=6.7 Hz, 2H), 1.02-0.87 (m,1H), 0.44-0.24 (m, 2H), 0.11-−0.07 (m, 2H).

Step-4: Preparation of[(3-{[2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-phenyl)-naphthalen-1-yl-methyl]-cyclopropylmethyl-carbamicAcid Tert-Butyl Ester (129e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenyl}-amide(129d) (0.60 g, 1.04 mmol) in MeOH (12 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.29 g, 1.24 mmol) and Bocanhydride (0.713 g, 3.11 mmol) followed by portionwise addition ofsodium borohydride (0.23 g, 6.21 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (0.28 mL, 2.59 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish[3-(5-{3-[(Cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (129e) (0.24 g, 34.46%).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenyl}-amide(129f)

To a solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenylcarbamoyl}-3-trifluoromethyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (129e) (0.240 g, 0.358 mmol) in methanol (10 mL)and added conc. HCl (0.5 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuum to dryness. The residuewas azeotroped with toluene (2×10 mL) and ethanol (10 mL), dried invacuum pump to furnish a white solid residue. The residue was purifiedby flash column chromatography (silica gel 12 g, eluting with 0-15%methanol in dichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-naphthalen-1-yl-methyl]-phenyl}-amide(129f) (0.08 g, 39.28%) free base as Light cream solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.93 (s, 1H), 10.25 (s, 1H), 10.00 (s, 1H), 8.46 (s, 3H),8.20 (d, J=7.8 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H),7.73-7.47 (m, 13H), 7.43-7.38 (m, 1H), 6.44 (t, J=6.1 Hz, 1H), 4.11 (q,J=5.6 Hz, 2H), 3.03-2.74 (m, 2H), 1.20-1.14 (m, 1H), 0.55 (dd, J=7.8,3.4 Hz, 2H), 0.39-0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.79; MS(ES+) 570.3 (M+1); (ES−) 604.3 (M+Cl);1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(129f) (0.28 g, 0.492 mmol) from above was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% methanol inchloroform) and converted to hydrochloride salt by dissolving theproduct obtained in methanol (5 mL) and treating it with 10 equivalentsof conc HCl. The solution obtained was concentrated in vacuum to drynessdried in vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(129f) hydrochloride as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H), 10.38 (s, 1H), 10.10 (d, J=10.5 Hz, 1H), 8.56 (s, 4H),8.30-8.20 (m, 2H), 8.00 (dd, J=7.0, 3.2 Hz, 2H), 7.91 (t, J=1.9 Hz, 1H),7.75-7.62 (m, 7H), 7.61-7.46 (m, 4H), 7.41 (t, J=7.9 Hz, 1H), 6.44 (t,J=6.2 Hz, 1H), 4.11 (q, J=5.6 Hz, 2H), 2.97-2.68 (m, 3H), 1.30-1.17 (m,1H), 0.55 (dd, J=7.9, 3.6 Hz, 2H), 0.41-0.21 (m, 2H); ¹⁹F NMR (282 MHz,DMSO) δ −60.78; MS (ES+) 570.3 (M+1); (ES−) 604.3 (M+Cl); Analysiscalculated for C₃₃H₃₀F₃N₅O.2HCl.2.25H₂O: C, 58.02; H, 5.39; Cl, 10.38;N, 10.25; Found; C, 57.93; H, 5.30; Cl, 10.28; N, 10.01.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130g) Step-1: Preparation of(3-amino-4-fluorophenyl)(4-nitrophenyl)methanol (130b)

To a stirred solution of 4-nitrobenzaldehyde (130a) (1.813 g, 12 mmol)in tetrahydrofuran (15 mL) cooled to 0° C. was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(18.00 mL, 18.00 mmol) and stirred at room temperature for 3 h. Reactionwas quenched with hydrochloric acid (10 mL, 2N) and stirred for 30 mins.To the reaction was basified with sodium bicarbonate solution andextracted with ethyl acetate (2×250 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL) dried andconcentrated in vacuum. The crude residue was purified by flash columnchromatography (silica gel 80 g, eluting with ethyl acetate in hexanes0-100%) to afford (3-amino-4-fluorophenyl)(4-nitrophenyl)methanol (130b)(1.71 g, 6.52 mmol, 54.3% yield) as an oil; ¹HNMR (300 MHz, DMSO-d₆) δ8.22-8.14 (m, 2H), 7.65-7.58 (m, 2H), 6.90 (dd, J=11.5, 8.2 Hz, 1H),6.76 (dd, J=9.0, 2.2 Hz, 1H), 6.12 (d, J=3.9 Hz, 1H, D₂O exchangeable),5.69 (d, J=3.8 Hz, 1H), 5.13 (s, 2H, D₂O exchangeable). MS (ES−) 261.1(M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.011 g, 7.15 mmol) in DMF (20 mL) was(3-amino-4-fluorophenyl)(4-nitrophenyl)methanol (130b) (1.705 g, 6.50mmol), N-ethyl-N-isopropylpropan-2-amine (5.66 mL, 32.5 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 3.64 g,7.80 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 37 h under nitrogen atmosphere. The reaction was dilutedwith water (75 mL) and extracted with ethyl acetate (2×75 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and evaporated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130c) (2.081 g, 3.96 mmol, 60.9% yield) as a brown semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.19 (dd, J=8.9, 2.5 Hz, 2H), 8.12(t, J=1.8 Hz, 1H), 8.02-7.97 (m, 1H), 7.93-7.87 (m, 1H), 7.78-7.69 (m,2H), 7.68-7.63 (m, 2H), 7.63-7.53 (m, 1H), 7.35-7.20 (m, 2H), 6.36 (d,J=4.0 Hz, 1H), 5.88 (d, J=3.9 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.98, −122.64; MS (ES+) 548.2 (M+Na); (ES−) 524.2 (M−1).

Step-3: Preparation of tert-butyl3-(5-((5-((4-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130d)

A solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130c) (2.119 g, 4.03 mmol) in MeOH (60 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (3.56 g, 16.13 mmol), nickel(II)chloride hexahydrate (0.516 g, 2.170 mmol) followed by portion-wiseaddition of sodium borohydride (1.557 g, 40.3 mmol) slowly over 5 min.the reaction was stirred at room temperature for 3 h, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.995 mL, 18.28 mmol) and stirredfor 30 mins. Reaction was concentrated to dryness. The residue wasdiluted with water (200 mL). The solid separated was collected byfiltration and purified by flash column chromatography [silica gel 40 g,eluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford tert-butyl3-(5-((5-((4-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130d) (0.815 g, 1.165 mmol, 28.9% yield) as a colorless foam; MS (ES+)722.4 (M+Na), (ES−) 698.3 (M−1) and tert-butyl3-(5-(5-((4-aminophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130e) (0.35 g, 0.584 mmol, 14.47% yield) as a colorless foam; MS (ES+)622.3 (M+Na), (ES−) 598.3 (M−1).

Step-4: Preparation of tert-butyl3-(5-((5-((4-tertbutoxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130f)

To a solution of3-(5-((5-((4-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130d) (0.798 g, 1.141 mmol) in dichloromethane (25 mL) at 0° C. addedthionyl chloride (0.178 mL, 2.435 mmol) and stirred at room temperaturefor 2 h. The reaction was treated with triethyl amine (1.7 mL, 12.19mmol) stirred at room temperature for 1 h. The reaction was diluted withcyclopropylmethanamine (2.084 mL, 24.32 mmol) and concentrated to removemost of dichloromethane followed by addition of acetonitrile (25.00 mL)and stirring at reflux for 16 h. Reaction was concentrated to drynesstreated with chloroform (240 mL), washed with water (100 mL), dried overMgSO₄ followed by filtration and concentration. Reaction was purified byflash column chromatography (silica gel, eluting with methanol inchloroform 0 to 20%) to afford tert-butyl3-(5-((5-((4-tertbutoxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130f) (297 mg, 0.395 mmol, 34.6% yield) as a yellow oil; MS (ES+) 753.5(M+1), (ES−) 751.3 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130g)

To a solution of afford tert-butyl3-(5-((5-((4-tertbutoxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(130f) (290 mg, 0.385 mmol) in methanol (5 mL) was added hydrochloricacid (1.170 mL, 38.5 mmol) and stirred at room temperature over night.The reaction mixture was concentrated in vacuum to dryness. The residuewas dried in a vacuum pump and purified by flash column chromatography(silica gel 12 g, eluting with 0-100% CMA 80 in chloroform) to affordcompound1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130g) (60 mg, 0.109 mmol, 28.2% yield) free base as a white solid. To astirred solution of free base of1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(130g) (60 mg, 0.109 mmol) in methanol (5 mL) was added conc.hydrochloric acid (0.045 mL, 0.543 mmol) and concentrated to removeexcess solvents and dried under vacuum to afford1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide130g (67.5 mg, 0.108 mmol, 99% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H, D₂O exchangeable),10.28 (s, 2H, D₂O exchangeable), 8.54 (s, 3H, D₂O exchangeable), 7.93(dd, J=7.2, 2.3 Hz, 1H), 7.79-7.68 (m, 5H), 7.65 (dt, J=7.3, 1.8 Hz,1H), 7.60-7.51 (m, 2H), 7.44-7.34 (m, 1H), 7.22 (d, J=8.1 Hz, 2H),5.71-5.58 (m, 1H), 4.12 (q, J=5.7 Hz, 2H), 2.70 (d, J=9.0 Hz, 2H), 1.17(ddt, J=12.8, 8.1, 4.1 Hz, 1H), 0.59-0.50 (m, 2H), 0.31 (td, J=5.8, 4.2Hz, 2H).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(131b) Step-1: Preparation of tert-butyl3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(131a)

To a solution of tert-butyl3-(5-((5-((3-tertbutyloxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(57c) (0.582 g, 0.832 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.130 mL, 1.776 mmol) and stirred at roomtemperature for 2 h. The reaction was treated with triethyl amine (0.771mL, 5.53 mmol) and stirred at room temperature for 1 h. The reaction wastreated with cyclopropylmethanamine (1.520 mL, 17.73 mmol) andconcentrated in vacuum to remove most of dichloromethane followed byaddition of acetonitrile (20.00 mL) and stirring at reflux for 16 h.Reaction was concentrated in vacuum to dryness dissolved in chloroform(300 mL), washed with water (100 mL), dried over MgSO₄ followed byfiltration and concentration. Reaction was purified by flash columnchromatography (silica gel 25 g, eluting with methanol in chloroform 0to 20%) to afford tert-butyl3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(131a) (115 mg, 0.153 mmol, 18.37% yield) as a white foam; MS (ES+)753.5 (M+1); (ES−) 751.4 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(131b)

To a solution of tert-butyl3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(131a) (115 mg, 0.153 mmol) in methanol (5 mL) was added hydrochloricacid (0.464 mL, 15.27 mmol) and stirred at room temperature overnight.The reaction mixture was concentrated in vacuum to dryness. The residuewas dried in vacuum pump and purified by flash column chromatography(silica gel 12 g, eluting with 0-100% CMA 80 in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(131b) as a free base. To a stirred solution of free base of compound131b (80 mg, 0.145 mmol) in methanol (5 mL) was added conc. hydrochloricacid (0.060 mL, 0.724 mmol) stirred for 30 mins and concentrated invacuum to dryness to afford pure1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(131b) (19 mg, 20.98% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.87 (s, 1H, D₂O exchangeable), 10.30 (s, 2H, D₂Oexchangeable), 8.55 (s, 3H, D₂O exchangeable), 7.91 (dd, J=7.4, 2.3 Hz,1H), 7.79-7.70 (m, 3H), 7.70-7.61 (m, 2H), 7.60-7.48 (m, 2H), 7.46 (d,J=8.5 Hz, 1H), 7.43-7.34 (m, 2H), 7.18 (d, J=7.9 Hz, 1H), 5.81-5.56 (m,1H), 4.11 (d, J=5.6 Hz, 2H), 2.77-2.66 (m, 2H), 1.17 (td, J=9.7, 7.6,4.3 Hz, 1H), 0.60-0.51 (m, 2H), 0.31 (dt, J=6.6, 4.6 Hz, 2H); MS (ES+)553.3 (M+1), 575.3 (M+23), (ES−) 587.3 (M+35).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132f) Step-1: Preparation of(3-amino-4-fluorophenyl)(pyridin-4-yl)methanol (132b)

To a stirred solution of isonicotinaldehyde (132a) (1.285 g, 12 mmol) inTetrahydrofuran (15 mL) at 0° C. was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(6.46 g, 18.0 mmol) and stirred at room temperature for 3 h. Thereaction was quenched with hydrochloric acid (10 mL, 2N) and stirred for30 mins. The reaction was basified with sodium bicarbonate solution andextracted with ethyl acetate (2×250 mL). The combined organic layers waswashed with water (2×50 mL), brine (50 mL) dried and concentrated invacuum. The crude residue was purified by flash column chromatography(silica gel 80 g, eluting with CMA 80 in chloroform) to afford(3-amino-4-fluorophenyl)(pyridin-4-yl)methanol (132b) (2.1 g, 80% yield)as a pale yellow solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.58-8.53 (m, 1H),8.42 (dd, J=4.8, 1.7 Hz, 1H), 7.71-7.64 (m, 1H), 7.32 (ddd, J=7.8, 4.8,0.9 Hz, 1H), 6.90 (dd, J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=9.0, 2.2 Hz,1H), 6.53 (ddd, J=8.3, 4.4, 2.2 Hz, 1H), 5.97 (d, J=3.9 Hz, 1H, D₂Oexchangeable), 5.62 (d, J=3.7 Hz, 1H), 5.12 (s, 2H, D₂O exchangeable);Mass spec (ES+) 219.2, 241.1 (M+23), (ES−) 217.1 (M−1).

Step-2: Preparation of1-(3-Cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.88 g, 10.25 mmol) in DMF (20 mL) was added(3-amino-4-fluorophenyl)(pyridin-4-yl)methanol (132b) (2.034 g, 9.32mmol), N-ethyl-N-isopropylpropan-2-amine (8.12 mL, 46.6 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 5.21 g,11.18 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 37 h under nitrogen atmosphere. The reaction wasdiluted with water (75 mL) and extracted with ethyl acetate (2×75 mL).The organic layers were combined, washed with brine (50 mL), dried,filtered, and evaporated in vacuum to dryness. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting with0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132c) (2.081 g, 4.32 mmol, 46.4% yield) as a yellow oil; ¹H NMR (300MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.51-8.47 (m, 2H), 8.15-8.10 (m, 1H),8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.93-7.87 (m, 1H), 7.76-7.69 (m, 2H), 7.55(dd, J=7.4, 2.1 Hz, 1H), 7.38-7.35 (m, 2H), 7.34-7.21 (m, 2H), 6.27 (d,J=4.0 Hz, 1H), 5.73 (d, J=4.1 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.99, −122.63; MS (ES+) 482.2 (M+Na).

Step-3: Preparation of tert-butyl3-(5-((2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132d)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132c) (3.44 g, 7.15 mmol) in MeOH (100 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (6.30 g, 28.6 mmol) and nickel(II)chloride hexahydrate (2.123 g, 8.93 mmol) followed by addition of sodiumborohydride (1.655 g, 42.9 mmol) slowly over 5 min and stirred at roomtemperature for 3 h. The reaction was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (9.36 mL, 86 mmol) stirred at roomtemperature for 0.5 h and concentrated in vacuum to dryness. The residuewas diluted with water (200 mL). The solid separated was collected byfiltration purified by flash column chromatography (silica gel 40 g,eluting with ethyl acetate in hexane 0-100%) to furnish tert-butyl3-(5-((2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132d) (1.172 g, 2.002 mmol, 27%) as an off white solid; MS (ES+) 586.3(M+1); (ES−) 584.3 (M−1).

Step-4: Preparation of tert-butyl3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132e)

To a solution of tert-butyl3-(5-((2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132d) (1.172 g, 2.002 mmol) in dichloromethane (40 mL) at 0° C. wasadded thionyl chloride (0.312 mL, 4.27 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched withtriethylamine (1.855 mL, 13.31 mmol) concentrated in vacuum to dryness.The residue obtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (3.66 mL, 42.7 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in chloroform (100 mL),washed with water (100 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (silicagel 40 g, eluting 0-20% methanol in chloroform) afforded tert-butyl3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132e) (127 mg, 0.199 mmol, 9.94% yield) as a white foam; MS (ES+) 639.4(M+1), (ES−) 637.4 (M−1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132f)

To a solution of tert-butyl3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(132e) in methanol (5 mL) was added hydrochloric acid (0.571 mL, 18.79mmol) and stirred at room temperature over night. The reaction mixturewas concentrated in vacuum to dryness. The residue was purified by flashcolumn chromatography (silica gel 12 g, eluting with 0-100% CMA 80 inchloroform) to afford compound free base of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132f). To a stirred solution of free base of1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(36 mg, 0.067 mmol) in methanol (5 mL) was added conc. hydrochloric acid(0.028 mL, 0.334 mmol) stirred for 30 mins and concentrated in vacuum todryness to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(132f) (30 mg, 0.049 mmol, 73.4% yield) hydrochloride salt as a yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.91 (s, 3H, D₂O exchangeable),8.95-8.84 (m, 2H), 8.56 (s, 3H, D₂O exchangeable), 8.33-8.21 (m, 2H),8.06 (dd, J=7.1, 2.3 Hz, 1H), 7.85 (ddd, J=8.6, 4.5, 2.3 Hz, 1H), 7.72(d, J=1.9 Hz, 2H), 7.65 (dt, J=7.3, 1.8 Hz, 1H), 7.60-7.49 (m, 2H), 7.44(dd, J=10.3, 8.6 Hz, 1H), 6.01 (s, 1H), 4.12 (q, J=5.8 Hz, 2H), 2.75 (d,J=6.9 Hz, 2H), 1.28-1.14 (m, 1H), 0.55 (m, 2H), 0.41-0.28 (m, 2H); MS(ES+) 539.3 (M+1), (ES−) 537.3 (M−1), 573.3 (M+35); Analysis calculatedfor C₂₈H₂₆F₄N₆O.3HCl.3H₂O: C, 47.98; H, 5.03; N, 11.99; Cl, 14.98;Found: C, 48.20; H, 5.00; N, 11.57; Cl, 14.20.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(biphenyl-4-yl(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(133g) Step-1: Preparation of (3-Amino-phenyl)-biphenyl-4-yl-methanol(133b)

To a stirred solution of biphenyl-4-carbaldehyde (133a) (1.2 g, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched with 2 N HCl (12.50 mL) and stirred for additional6 h. The reaction mixture was nuetralized with 2 N NaOH (15 mL),extracted with ethyl acetate (2×50 mL). The organic layers were combinedwashed with saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue obtained was purifiedby flash column chromatography (silica gel 40 g, eluting with 0-100%ethyl acetate in hexane) to furnish(3-Amino-phenyl)-biphenyl-4-yl-methanol (133b) (2.0 g, 72.64%) as alight brown sticky liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.64-7.55 (m,4H), 7.44 (ddt, J=8.4, 6.4, 1.8 Hz, 4H), 7.37-7.28 (m, 1H), 6.93 (t,J=7.7 Hz, 1H), 6.61 (t, J=1.9 Hz, 1H), 6.55 (dt, J=7.7, 1.3 Hz, 1H),6.39 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.74 (d, J=3.8 Hz, 1H), 5.55 (d,J=3.8 Hz, 1H), 5.00 (s, 2H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(biphenyl-4-yl-hydroxy-methyl)-phenyl]-amide (133c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.04g, 7.263 mmol) in DMF (40 mL) was added((3-Amino-phenyl)-biphenyl-4-yl-methanol (133b) (2.0 g, 7.26 mmol),N-ethyl-N-isopropylpropan-2-amine (10 mL, 58.10 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 3.38 g,7.26 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 42 h and diluted with ethyl acetate (350 mL). Thereaction mixture was washed with water (2×150 mL), brine (120 mL),dried, filtered, and evaporated to dryness. The residue obtained waspurified by flash column chromatography (silica gel 120 g, eluting withethyl acetate in hexanes from 0-30% to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(biphenyl-4-yl-hydroxy-methyl)-phenyl]-amide (133c) (2.0 g, 51.13%)as a red brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H),8.16 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2,2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.71 (d, J=4.8 Hz, 1H), 7.67(d, J=1.8 Hz, 1H), 7.64-7.54 (m, 5H), 7.44 (dd, J=8.4, 6.5 Hz, 4H),7.37-7.30 (m, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.21-7.15 (m, 1H), 6.01 (d,J=3.8 Hz, 1H), 5.73 (d, J=3.8 Hz, 1H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(biphenyl-4-yl-hydroxy-methyl)-phenyl]-amide (133c) (2.0 g, 3.71mmol) in dichloromethane (20 mL) at 0° C. was added thionyl chloride(0.883 g, 7.43 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (4.2 mL, 55.71 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (40mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133d)(1.0 g, 45.56%) as pale gummy liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66(s, 1H), 8.20-8.11 (m, 1H), 7.99 (dd, J=7.7, 1.6 Hz, 1H), 7.93-7.87 (m,1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=3.3 Hz, 2H), 7.63-7.52 (m, 5H),7.51-7.45 (m, 2H), 7.42 (d, J=7.7 Hz, 1H), 7.37-7.32 (m, 1H), 7.31-7.22(m, 2H), 4.87 (s, 1H), 2.32 (d, J=6.7 Hz, 2H), 1.03-0.87 (m, 1H),0.50-0.29 (m, 2H), 0.18-−0.04 (m, 2H).

Step-4: Preparation of tert-butyl([1,1′-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate(133e) and tert-butyl3-(5-((3-([1,1′-biphenyl]-4-yl((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(133f)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133d)(1.0 g, 1.69 mmol) in MeOH (24 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (0.48 g, 2.03 mmol) and Boc anhydride(1.16 mL, 5.07 mmol) followed by portion-wise addition of SodiumBorohydride (0.44 g, 10.14 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.5 mL, 4.23 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-40% Ethyl acetate/hexane) to furnish.

-   -   1. tert-butyl        ([1,1′-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate        (133e) (300 mg, 22.3%) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.73 (s, 1H), 7.72-7.63 (m, 5H), 7.55 (s, 1H),        7.52-7.38 (m, 7H), 7.38-7.30 (m, 3H), 7.26 (d, J=8.2 Hz, 2H),        7.01-6.93 (m, 1H), 6.33 (s, 1H), 4.18 (d, J=6.2 Hz, 2H), 3.12        (t, J=6.3 Hz, 2H), 1.37 (s, 9H), 1.32 (s, 9H), 0.92-0.77 (m,        1H), 0.20 (d, J=8.1 Hz, 2H), −0.15 (s, 2H).    -   2. tert-butyl        3-(5-((3-([1,1′-biphenyl]-4-yl((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (133f) (280 mg, 23.81%) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.71 (s, 1H), 7.71-7.67 (m, 1H), 7.63-7.55 (m, 5H),        7.53-7.46 (m, 3H), 7.45-7.39 (m, 4H), 7.38-7.32 (m, 3H), 7.25        (d, J=6.7 Hz, 2H), 4.87 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.32        (d, J=6.7 Hz, 2H), 1.35 (s, 9H), 0.99-0.89 (m, 1H), 0.47-0.32        (m, 2H), 0.12-−0.02 (m, 2H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133g)

A solution of tert-butyl([1,1′-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate(133e) (300 mg, 0.37 mmol) and tert-butyl3-(5-((3-([1,1′-biphenyl]-4-yl((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(133f) (280 mg, 0.4 mmol) were dissolved separately in methanol (10 mL)and added conc. HCl (0.5 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuum to dryness. The residuewas azeotroped with toluene (2×10 mL) and ethanol (10 mL), dried invacuum pump to furnish a white solid residue. NMR of the residue inmethanol and TLC shows same compound. The products were combined driedand purified by flash column chromatography (silica gel 24 g, elutingwith 0-15% methanol in dichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133g)(0.250 g, 54.56%) as pale white solid. This was repurified by flashcolumn chromatography (silica gel 4 g, eluting 0-25% methanol inchloroform) to afford2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[biphenyl-4-yl-(cyclopropylmethyl-amino)-methyl]-phenyl}-amide (133g)(0.14 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.19 (d, J=6.8 Hz, 2H), 8.51 (s, 3H), 7.92 (s, 1H), 7.81-7.59 (m, 12H),7.56-7.43 (m, 4H), 7.39 (d, J=7.2 Hz, 1H), 5.75-5.56 (m, 1H), 4.12 (q,J=5.6 Hz, 2H), 2.75 (q, J=5.7, 4.9 Hz, 2H), 1.19 (td, J=13.0, 10.7, 5.7Hz, 1H), 0.57 (d, J=7.6 Hz, 2H), 0.42-0.20 (m, 2H); ¹⁹F NMR (282 MHz,DMSO) δ −60.77; MS (ES+) 596.4 (M+1); (ES−) 630.3 (M+Cl); Analysiscalculated for C₃₅H₃₂F₃N₅O.2.5HCl.2H₂O: C, 58.16; H, 5.37; Cl, 12.26; N,9.69; Found; C, 58.11; H, 5.19; Cl, 11.86; N, 9.47.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(6-methoxynaphthalen-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(134f) Step-1: Preparation of(3-Amino-phenyl)-(6-methoxy-naphthalen-2-yl)-methanol (134b)

To a stirred solution of 6-Methoxy-naphthalene-2-carbaldehyde (134a)(1.2 g, 10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h quenched with 2 NHCl (12.50 mL) and stirred for additional 6 h at room temperature. Thereaction mixture was basified with 2 N NaOH (15 mL) and extracted withethyl acetate (2×50 mL). The organic layers were combined washed withsaturated NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-Amino-phenyl)-(6-methoxy-naphthalen-2-yl)-methanol(134b) (2.4 g, 85.92%) as a light brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.82-7.75 (m, 2H), 7.71 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8.5,1.7 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.12 (dd, J=9.0, 2.5 Hz, 1H), 6.92(t, J=7.7 Hz, 1H), 6.60 (t, J=1.9 Hz, 1H), 6.56 (dt, J=7.6, 1.3 Hz, 1H),6.38 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.77 (d, J=3.7 Hz, 1H), 5.63 (d,J=3.8 Hz, 1H), 4.97 (s, 2H), 3.85 (s, 3H).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide (134c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.6g, 9.45 mmol) in DMF (48 mL) was added(3-Amino-phenyl)-(6-methoxy-naphthalen-2-yl)-methanol (134b) (2.4 g,8.59 mmol), N-ethyl-N-isopropylpropan-2-amine (8.88 g, 68.72 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 4.40 g,9.451 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 42 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (200 mL) washed with water (2×100 mL), brine(100 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-30%] to furnish2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide (134c)(2.4 g, 51.50% yield) as a red brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.63 (s, 1H), 8.14 (t, J=1.9 Hz, 1H), 7.99 (dt, J=7.8, 1.3Hz, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84-7.82 (m, 1H), 7.79 (d,J=9.0 Hz, 1H), 7.76-7.67 (m, 3H), 7.65 (t, J=1.8 Hz, 1H), 7.56 (dt,J=8.2, 1.5 Hz, 1H), 7.37 (dd, J=8.5, 1.7 Hz, 1H), 7.29 (d, J=7.8 Hz,1H), 7.27-7.23 (m, 1H), 7.19 (dt, J=7.9, 1.4 Hz, 1H), 7.14 (dd, J=8.9,2.5 Hz, 1H), 6.03 (d, J=3.8 Hz, 1H), 5.80 (d, J=3.8 Hz, 1H), 3.85 (s,3H).

Step-3: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid{3-[(cyclopropylmethyl-amino)-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide(134d)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide (134c)(2.4 g, 4.42 mmol) in dichloromethane (50 mL) at 0° C. was added thionylchloride (1.05 g, 8.85 mmol) and stirred at room temperature for 4 h.The reaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (4.72 g, 66.3 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (40mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide(134d) (1.3 g, 49.38%) as light brown sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.63 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7.8, 1.3Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H),7.77 (d, J=9.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.72-7.68 (m, 4H), 7.55(td, J=4.7, 2.1 Hz, 1H), 7.46 (dd, J=8.5, 1.7 Hz, 1H), 7.25 (t, J=4.0Hz, 3H), 7.13 (dd, J=8.9, 2.6 Hz, 1H), 4.95 (s, 1H), 3.84 (s, 3H), 2.33(d, J=6.7 Hz, 2H), 1.24 (s, 1H), 0.89-0.79 (m, 1H), 0.44-0.31 (m, 2H),0.05 (q, J=4.8 Hz, 2H).

Step-4: Preparation of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(6-methoxynaphthalen-2-yl)methyl)(cyclopropylmethyl)carbamate(134e)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide(134d) (1.3 g, 2.18 mmol) in MeOH (26 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.62 g, 2.619 mmol) and Bocanhydride (1.5 mL, 6.547 mmol) followed by portion-wise addition ofsodium borohydride (0.500 g, 13.095 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (0.6 mL, 5.456 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% Ethyl acetate/hexane) to furnishtert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(6-methoxynaphthalen-2-yl)methyl)(cyclopropylmethyl)carbamate(134e) (0.90 g, 51.57%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H), 7.80 (d, J=5.7 Hz, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.67 (d,J=8.1 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.53 (s, 1H), 7.47 (q, J=6.4 Hz,2H), 7.39 (t, J=3.7 Hz, 2H), 7.33 (dd, J=7.4, 2.3 Hz, 4H), 7.14 (dd,J=9.0, 2.5 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 4.17 (d, J=6.1Hz, 2H), 3.87 (s, 3H), 3.14 (d, J=6.6 Hz, 2H), 1.37 (s, 9H), 1.32-1.29(m, 9H), 0.68-0.50 (m, 1H), 0.23-0.04 (m, 2H), −0.06-−0.21 (m, 1H),−0.18-−0.31 (m, 1H).

Step-5: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid{3-[(cyclopropylmethyl-amino)-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide(134f)

To a solution of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(6-methoxynaphthalen-2-yl)methyl)(cyclopropylmethyl)carbamate(134e) (0.90 g, 1.13 mmol) in methanol (10 mL) was added conc. HCl (0.5mL). The reaction mixture was stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue was azeotroped withtoluene (2×10 mL) and ethanol (10 mL), dried in vacuum pump to furnish awhite solid residue. The product was purified by flash columnchromatography (silica gel 12 g, eluting with 0-15% methanol indichloromethane to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-(6-methoxy-naphthalen-2-yl)-methyl]-phenyl}-amide(BCX-7246, 155 mg, 20.5%) as off white solid. This was repurified byflash column chromatography (silica gel 4 g, eluting 0-25% methanol inchloroform) to afford pure1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(6-methoxynaphthalen-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(134f) (0.085 g) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s,1H), 10.30-10.12 (m, 2H), 8.52 (s, 3H), 8.14 (d, J=2.0 Hz, 1H), 7.91 (t,J=1.8 Hz, 1H), 7.84 (dd, J=16.4, 8.9 Hz, 2H), 7.77-7.68 (m, 4H), 7.63(tt, J=5.8, 1.7 Hz, 2H), 7.57-7.42 (m, 3H), 7.34 (d, J=2.6 Hz, 1H), 7.22(dd, J=8.9, 2.5 Hz, 1H), 5.82-5.57 (m, 1H), 4.11 (d, J=5.6 Hz, 2H), 3.87(s, 3H), 2.81-2.66 (m, 2H), 1.20 (td, J=8.0, 3.9 Hz, 1H), 0.62-0.45 (m,2H), 0.40-0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+) (ES−)634.3 (M+Cl); Analysis calculated for C₃₄H₃₂F₃N₅O₂.2HCl.2H₂O: C, 57.63;H, 5.41; Cl, 10.01; N, 9.88; Found: C, 57.50; H, 5.11; Cl, 9.86; N,9.68.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(135c) Step-1: Preparation of tert-Butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(4-hydroxyphenyl)methyl)(cyclopropylmethyl)carbamate(135a) and tert-Butyl3-(5-((3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(135b)

To a solution of1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123d) (1.2 g, 2.26 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.57 g, 2.4 mmol) and Bocanhydride (1.26 g, 5.79 mmol) followed by portionwise addition of sodiumborohydride (0.44 g, 11.58 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.1 mL, 7.72 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-60% Ethyl acetate/hexane) to furnish:

-   -   1. tert-Butyl        ((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(4hydroxyphenyl)methyl)(cyclopropylethyl)        carbamate (135a) (0.167 g, 7.55%) as a white solid; ¹H NMR (300        MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.47 (s, 1H), 7.68-7.58 (m, 1H),        7.55 (s, 1H), 7.53-7.45 (m, 1H), 7.46-7.37 (m, 2H), 7.37-7.25        (m, 3H), 6.97 (dd, J=8.4, 6.5 Hz, 2H), 6.92-6.85 (m, 1H),        6.77-6.70 (m, 2H), 6.22 (s, 1H), 4.25-4.13 (m, 2H), 3.12 (dd,        J=14.5, 6.7 Hz, 1H), 2.95 (dd, J=14.5, 6.6 Hz, 1H), 1.37 (s,        9H), 1.31 (s, 9H), 0.58 (d, J=25.7 Hz, 1H), 0.17 (ddt, J=13.6,        9.2, 4.4 Hz, 2H), −0.11 (dd, J=9.0, 4.6 Hz, 1H), −0.30 (s, 1H);        ¹⁹F NMR (282 MHz, DMSO) δ −60.78; MS (ES+) 736.5 (M+1); (ES−)        734.1 (M−1).    -   2. tert-Butyl        3-(5-((3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)        carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (135b) (0.209 g, 10.93%) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.67 (s, 1H), 9.23 (s, 1H), 7.60 (d, J=2.1 Hz, 1H),        7.57 (s, 1H), 7.55-7.46 (m, 1H), 7.42 (dd, J=9.9, 3.1 Hz, 2H),        7.37-7.31 (m, 2H), 7.22 (t, J=7.8 Hz, 1H), 7.18-7.13 (m, 3H),        6.68-6.62 (m, 2H), 4.69 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.26        (d, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.00-0.81 (m, 1H), 0.41-0.32        (m, 2H), 0.07-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS        (ES+) 636.4 (M+1); (ES−) 634.4 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(135c)

To a solution of tert-butyl3-(5-(3-((cyclopropylmethylamino)(4-hydroxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(135b) (0.199 g, 0.313 mmol) in methanol (3 mL) was added aq. 12 N HCl(0.652 mL, 7.83 mmol), the solution was stirred at 50° C. for 6 h andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with 0-50%methanol in chloroform) to afford (135c) (39 mg, 23% yield) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H, D₂O exchangeable), 9.74 (s,1H, D₂O exchangeable), 8.43 (s, 3H, D₂O exchangeable), 7.80 (s, 1H),7.73 (d, J=2.1 Hz, 1H), 7.69 (s, 1H), 7.66-7.48 (m, 5H), 7.47-7.33 (m,3H), 6.78 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.12 (s, 2H), 2.65 (s, 2H),1.11 (d, J=11.2 Hz, 1H), 0.54 (d, J=8.0 Hz, 2H), 0.27 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.78; MS (ES⁺): MS (ES+) 536.3 (M+1), MS (ES−)570.2 (M+Cl); Analysis calculated for: C₂₉H₂₈F₃N₅O₂.2.5H₂O.2.35HCl: C,52.28; H, 5.35; Cl, 12.50; N, 10.51; Found: C, 52.16; H, 5.25; Cl,12.39; N, 10.30.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(4-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(136a)

To a solution of1-(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123f) (0.2 g, 0.320 mmol) in methanol (30 mL) was added hydrogenchloride (4N in dioxane, 0.799 mL, 3.20 mmol) and palladium (10% Pd oncarbon) (0.102 g, 0.096 mmol). The reaction mixture was hydrogenated at60 psi for 14 h. The reaction mixture was filtered through a smallCelite pad and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel, 12 gm eluting with 0-25%methanol in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-(4-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(136a) (0.211 g) hydrochloride salt as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.26 (s, 1H), 8.39 (s, 3H), 7.71 (t,J=1.7 Hz, 1H), 7.65 (d, J=0.7 Hz, 1H), 7.62 (dt, J=7.4, 1.6 Hz, 1H),7.56 (d, J=7.8 Hz, 1H), 7.51 (ddd, J=5.7, 3.5, 1.5 Hz, 2H), 7.44 (t,J=1.9 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.02-6.94 (m, 3H), 6.74-6.63 (m,2H), 4.12 (s, 2H), 3.79 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS(ES+) 467.3 (M+1); (ES−) 501.2 (M−1); Analysis calculated forC₂₅H₂₁F₃N₄O₂.HCl.H₂O: C, 57.64; H, 4.64; Cl, 6.81; N, 10.76; Found; C,57.91; H, 4.75; Cl, 6.96; N, 10.64.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(137a) and1-(3-(aminomethyl)phenyl)-N-(3-(3-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(137b)

To a solution of1-(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(107f) (0.31 g, 0.495 mmol) in methanol (30 mL) was added hydrogenchloride (4N in dioxane, 1.239 mL, 4.95 mmol) and palladium (10% Pd oncarbon) (0.158 g, 0.149 mmol). The reaction mixture was hydrogenated at60 psi for 14 h at room temperature. The reaction mixture was filteredthrough a small Celite pad and concentrated in vacuum to dryness.

The residue obtained was purified by flash column chromatography (silicagel, 12 gm eluting with 0-25% methanol in chloroform) to afford

-   -   1.        1-(3-(aminomethyl)phenyl)-N-(3-(3-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (137b) (0.211 g, 0.452 mmol, 91% yield) as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.34 (s, 1H), 8.49-8.32 (m,        3H), 7.72 (t, J=1.7 Hz, 1H), 7.66 (s, 1H), 7.64-7.57 (m, 1H),        7.56-7.45 (m, 4H), 7.26 (t, J=7.8 Hz, 1H), 7.11-6.97 (m, 2H),        6.66-6.51 (m, 3H), 4.12 (q, J=5.8 Hz, 2H), 3.81 (s, 2H); ¹⁹F NMR        (282 MHz, DMSO) δ −60.79; MS (ES+) 467.3 (M+1); 489.2 (M+Na),        (ES−) 465.3 (M−1); 501.2 (M+Cl); Analysis calculated for        C₂₅H₂₁F₃N₄O₂.HCl.H₂O: C, 57.64; H, 4.64; Cl, 6.81; N, 10.76;        Found: C, 57.65; H, 4.64; Cl, 7.21; N, 10.68.    -   2.        1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (137a) (0.02 g, 0.037 mmol, 7.54% yield) as a hygroscopic solid;        ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.09 (s, 2H), 9.80        (s, 1H), 8.62 (s, 4H), 7.88-7.83 (m, 1H), 7.76 (s, 1H), 7.74 (d,        J=2.1 Hz, 1H), 7.69-7.60 (m, 3H), 7.58-7.48 (m, 2H), 7.42 (t,        J=7.9 Hz, 1H), 7.25-7.10 (m, 2H), 7.03-6.97 (m, 1H), 6.78 (ddd,        J=7.9, 2.4, 1.1 Hz, 1H), 5.44 (d, J=6.2 Hz, 1H), 4.11 (s, 3H),        2.78-2.59 (m, 2H), 1.17 (tt, J=7.8, 4.5 Hz, 1H), 0.63-0.44 (m,        2H), 0.32 (dt, J=6.5, 4.4 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ        −60.77; MS (ES+) 536.3 (M+1); (ES−) 570.3 (M−1); Analysis        calculated for C₂₉H₂₈F₃N₅O₂.2.5C₄H₉.2.5HCl.2.25HCl.3.25H₂O: C,        49.56; H, 6.59; Cl, 17.82; N, 11.12; Found: C, 49.81; H, 6.58;        Cl, 17.65; N, 10.70 (From NMR analysis and integration the        sample is contaminated with 2.5 equivalents of        cyclopropylmethylamine hydrochloride).

Preparation ofN-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138f) Step-1: Preparation ofN-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (138b)

To a stirred solution of N-(4-formylphenyl)acetamide (138a) (1 g, 6.13mmol) in tetrahydrofuran (7 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (7.40 mL,7.40 mmol) at 0° C. The reaction was stirred for 12 h quenched with 2 NHCl (15 mL) and stirred for additional 6 h at room temperature. Thereaction mixture was basified with 2 N NaOH (15 mL) and extracted withethyl acetate (2×50 mL). The organic layers were combined washed withsaturated NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography [silica gel 40 g, eluting with chloroform/methanol (1:0to 9:1)] to give N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide(138b) (1.455 g, 93%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.86 (s, 1H), 7.50-7.41 (m, 2H), 7.29-7.18 (m, 2H), 6.90 (t, J=7.7 Hz,1H), 6.54 (t, J=2.0 Hz, 1H), 6.51-6.46 (m, 1H), 6.37 (ddd, J=7.9, 2.3,1.1 Hz, 1H), 5.61 (d, J=3.8 Hz, 1H), 5.44 (d, J=3.8 Hz, 1H), 4.97 (s,2H), 2.00 (s, 3H); MS (ES+): 279.2 (M+Na).

Step-2: Preparation ofN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.514 g, 5.38 mmol) in DMF (27 mL) was added N-(4-((3aminophenyl)(hydroxy)methyl)phenyl)acetamide (138b) (1.38 g, 5.38 mmol),N-ethyl-N-isopropylpropan-2-amine (7.70 mL, 44.2 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 2.56 g,5.38 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 22 h under nitrogen atmosphere. The reaction was dilutedwith ethyl acetate (200 mL) washed with water (2×80 mL), brine (80 mL),dried, filtered, and evaporated to dryness. The residue obtained waspurified by flash column chromatography [silica gel 40 g, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to furnishN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138c) (2.28 g) as a yellow solid, which was used as such for next step.MS (ES+): 542.2 (M+Na).

Step-3: Preparation of tert-butyl3-(5-(3-((4-acetamidophenyl)-(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138d)

To a solution ofN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138c) (2.13 g, 4.10 mmol) in MeOH (70 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.524 g, 2.206 mmol) anddi-tert-butyl dicarbonate (3.62 g, 16.40 mmol) followed by portion-wiseaddition of sodium borohydride (1.583 g, 41.0 mmol) over a period of 15min. The reaction mixture was stirred at room temperature for 2 hrs andquenched with N¹-(2-aminoethyl)ethane-1,2-diamine (2.0 mL, 18.33 mmol)followed by stirring for additional 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was dissolvedin ethyl acetate (200 mL) and water (200 mL). The aqueous layer wasseparated extracted with ethyl acetate (200 mL). The combined extractswere washed with brine (100 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel 40 g, eluting with chloroform/methanol(1:0 to 9:1)] to give tert-butyl3-(5-(3-((4-acetamidophenyl)-(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138d) (1.284 g, 41% for 2 steps). ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s,1H), 9.88 (s, 1H), 7.60-7.20 (m, 13H), 7.11 (d, J=7.7 Hz, 1H), 5.86 (d,J=3.8 Hz, 1H), 5.60 (d, J=3.8 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.01 (s,3H), 1.37 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.79; MS (ES+): 646.3(M+Na).

Step-4: Preparation of tert-butyl3-(5-(3-((4-acetamidophenyl)(cyclopropyl-methylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138e)

To a solution of tert-butyl3-(5-(3-((4-acetamidophenyl)-(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138d) (0.218 g, 1.953 mmol) in dichloromethane (36 mL) at 0° C. wasadded thionyl chloride (0.3 mL, 4.05 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched with triethylamine (1.800 mL, 12.92 mmol), stirred for 1 h and concentrated in vacuumto dryness. The residue obtained was dissolved in acetonitrile (27 mL)and added cyclopropylmethanamine (3.70 mL, 41.4 mmol). The reactionmixture was heated at 70° C. for 14 h, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved inchloroform (240 mL), washed with water (100 mL), dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel 40 g, eluting with chloroform/methanol(1:0 to 19:1)] to give tert-butyl3-(5-(3-((4-acetamidophenyl)(cyclopropyl-methylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138e) (240 mg) as a white solid; MS (ES+): 677.4 (M+H).

Step-5: Preparation ofN-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138f)

To a solution of tert-butyl3-(5-(3-((4-acetamidophenyl)(cyclopropyl-methylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(138e) (227 mg, 0.335 mmol) in 1,4-Dioxane (22 mL) was added hydrogenchloride (3.70 mL, 14.79 mmol, 4 M in 1,4-dioxane). The reaction mixturewas stirred at room temperature for 16 h. The reaction mixture wastreated with hexanes, decanted, washed with hexanes, and decanted again.The insoluble crude product was purified by combiflash columnchromatography on silica gel with chloroform/CMA80 (1:0 to 2:1) to giveN-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(138f) (43 mg) free base as a white solid. The purified product (138f)(41 mg) was dissolved in methanol (10 mL) and treated with 4 N HCl (aq.0.08 mL) followed by concentration to dryness toN-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(43 mg, 3.8% for 2 steps) hydrochloride salt as a light yellow solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H), 10.14 (s, 1H), 9.85 (s, 2H),8.37 (s, 3H), 7.83 (s, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.67 (s, 1H),7.64-7.48 (m, 9H), 7.44 (t, J=7.9 Hz, 1H), 5.51 (t, J=5.5 Hz, 1H), 4.13(d, J=5.3 Hz, 2H), 2.78-2.63 (m, 3H), 2.04 (s, 3H), 1.12 (td, J=13.2,12.5, 7.0 Hz, 1H), 0.64-0.47 (m, 2H), 0.37-0.22 (m, 2H); ¹H NMR (300MHz, DMSO-d₆, D₂O exchange) δ 7.79 (t, 1H), 7.70 (t, 1H), 7.64-7.40 (m,11H), 5.51 (s, 1H), 4.13 (s, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.05 (s, 3H),1.16-0.98 (m, 1H), 0.64-0.54 (m, 2H), 0.32-0.24 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.79; MS (ES+): 577.3 (M+H); Analysis calculated forC₃₁H₃₁F₃N₆O₂.2HCl.3H₂O: C, 52.92; H, 5.59; N, 11.94; Found: 52.66; H,5.51; N, 11.56; C, 52.66; H, 5.51; N, 11.56.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(139b) Step-1: Preparation of tert-butyl3-(5-((5-((4-(tert-butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(139a)

To a solution of tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52g) (155 mg, 0.234 mmol) in MeOH (5 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (30.0 mg, 0.126 mmol) anddi-tert-butyl dicarbonate (206 mg, 0.936 mmol) followed by portion-wiseaddition of sodium borohydride (90 mg, 2.339 mmol) over a period of 15min. The reaction mixture was stirred at room temperature for 2 hrs andquenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.110 mL, 1.006 mmol)followed by stirring for additional 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was dissolvedin ethyl acetate (100 mL) and water (60 mL). The aqueous layer wasseparated extracted with ethyl acetate (60 mL). The combined extractswere washed with brine (60 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel 40 g, eluting with hexanes/ethylacetate (1:0 to 1:1)] to give tert-butyl3-(5-((5-((4-(tert-butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(139a) (70 mg, 39%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.54 (s, 1H), 7.68-7.10 (m, 14H), 4.81 (s, 1H), 4.19 (d, J=6.4 Hz, 2H),4.05 (d, J=6.7 Hz, 2H), 2.29-2.23 (m, 2H), 1.38 (s, 18H), 1.00-0.80 (m,1H), 0.43-0.28 (m, 2H), 0.07-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.81, −123.76; MS (ES+): 767.5 (M+H).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(139b)

To a solution of give tert-butyl3-(5-((5-((4-(tert-butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(139a) (60 mg) in 1,4-Dioxane (7 mL) was added hydrogen chloride (0.970mL, 3.88 mmol, 4 M in 1,4-dioxane) and stirred at room temperature for21 h. The reaction mixture was treated with hexanes, decanted, washedwith hexanes, and decanted again. The insoluble crude product waspurified by flash column chromatography [silica gel, eluting withchloroform/CMA80 (1:0 to 1:1)] to give1-(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(139b) (23 mg, 46%) free base as a colorless gum. The purified free base(139b) was dissolved in methanol (10 mL) and added 4 N HCl (aq. 0.04mL), stirred for 30 mins followed by concentration to dryness to give1-(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(139b) (31 mg) hydrochloride salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.83 (s, 1H), 10.29 (d, J=38.5 Hz, 0H), 8.40 (s, 6H), 7.95(s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.71 (d, J=4.4 Hz, 3H), 7.65-7.60 (m,1H), 7.57 (d, J=7.8 Hz, 1H), 7.55-7.50 (m, 3H), 7.40 (t, J=9.3 Hz, 1H),5.68 (s, 1H), 4.13 (s, 2H), 4.00 (s, 2H), 2.75-2.63 (m, 2H), 1.23-1.09(m, 1H), 0.56 (m, 2H), 0.30 (m, 2H); ¹H NMR (D₂O ex NMR, 300 MHz,DMSO-d₆) δ 7.89 (d, J=6.9 Hz, 1H), 7.74-7.48 (m, 10H), 7.42 (t, J=9.5Hz, 1H), 5.66 (s, 1H), 4.12 (s, 2H), 4.02 (s, 2H), 2.78-2.67 (m, 2H),1.14-1.00 (m, 1H), 0.59 (d, J=7.8 Hz, 2H), 0.28 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.82, −120.56; MS (ES+): 567.3 (M+1); Analysiscalculated for C₃₀H₃₀F₄N₆O.3HCl.4H₂O: C, 48.17; H, 5.52; N, 11.23.;Found: C, 47.79; H, 5.78; N, 10.84.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(m-tolyl)methy)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140e) Step-1: Preparation of (3-amino-4-fluorophenyl)(m-tolyl)methanol(140a)

To a stirred solution of 3-methylbenzaldehyde (110a) (1.179 mL, 10 mmol)in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(18.00 mL, 18.00 mmol) at 0° C. The reaction was stirred for 14 h atsame temperature and quenched by adding 2 N HCl (10 mL, 20 mmol),stirred for 0.5 h. The reaction mixture was basified by aqueous NaHCO₃and extracted with ethyl acetate (2×250 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL) dried over anhydrousMgSO₄, filtered, evaporated to dryness. The crude residue was purifiedby flash column chromatography (silica gel 80 g, eluting with ethylacetate in hexane from 0-100%) to afforded(3-amino-4-fluorophenyl)(m-tolyl)methanol (140a) (1.771 g, 7.66 mmol,51.1% yield) as a light yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.23-7.06 (m, 3H), 7.00 (dt, J=7.1, 1.7 Hz, 1H), 6.86 (dd, J=11.5, 8.3Hz, 1H), 6.75 (dd, J=9.0, 2.1 Hz, 1H), 6.49 (ddd, J=8.3, 4.5, 2.2 Hz,1H), 5.70 (d, J=3.8 Hz, 1H, D₂O exchangeable), 5.48 (d, J=3.7 Hz, 1H),5.05 (s, 2H, D₂O exchangeable), 2.26 (s, 3H); Mass spec (ES+) 254.1(M+24); (ES−) 230.1 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140b)

In a 100 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.341 g, 8.32 mmol), (3-amino-4-fluorophenyl)(m-tolyl)methanol (140a)(1.75 g, 7.57 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (4.23 g, 9.08 mmol) was addedN,N-dimethylformamide (20 mL) and N-ethyl-N-isopropylpropan-2-amine(DIPEA, 6.59 mL, 37.8 mmol) successively in a positive flow of nitrogenat room temperature. The resulting reaction mixture was stirred at roomtemperature for 20 h under a positive flow of nitrogen atmosphere. Thereaction was diluted with water (100 mL) and extracted with ethylacetate (2×200 mL). The organic layers were combined, washed with water(2×100 mL), brine (50 mL), dried, filtered, and evaporated in vacuum todryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexanes) to afford1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140b) (2.29 g, 4.63 mmol, 61.2% yield) as a yellow semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.16-8.10 (m, 1H),8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.93-7.86 (m, 1H), 7.77-7.68 (m, 2H), 7.50(d, J=7.2 Hz, 1H), 7.30-7.10 (m, 5H), 7.05-6.98 (m, 1H), 5.96 (d, J=3.9Hz, 1H, D₂O exchangeable), 5.64 (d, J=3.9 Hz, 1H), 2.26 (s, 3H); MS(ES+) 517.2 (M+Na), (ES−) 493.2 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140c)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(m-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140b) (2.12 g, 4.29 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.668 mL, 9.15 mmol), stirred at room temperature for2 h and quenched with triethylamine (3.97 mL, 28.5 mmol). The reactionmixture was stirred for 1 h and added cyclopropylmethanamine (7.83 mL,91 mmol) and concentrated in vacuum to remove dichloromethane. Theresidue obtained was dissolved in acetonitrile (20 mL) and addedcyclopropylmethanamine (7.83 mL, 91 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in chloroform (300 mL),washed with water (100 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (silicagel 25 g, eluting with CMA 80 in chloroform 0 to 20%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140c) (1.3 g, 2.374 mmol, 55.4% yield) as an oil; MS (ES+) 548.3 (M+1),(ES−) 546.3 (M−1).

Step-4: Preparation of tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(140d)

To a solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140c) (1.25 g, 2.283 mmol) in MeOH (25 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.993 g, 9.13 mmol) and nickel(II)chloride (0.136 g, 0.571 mmol). Sodium Borohydride (0.818 g, 22.83 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.110 mL, 10.27 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdiluted with water (200 mL). The solid separated was collected byfiltration and purified by flash column chromatography [silica gel 40 g,eluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(140d) (0.864 g, 1.326 mmol, 58.1% yield) as a white solid.

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140e)

To a solution of tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(140d) (0.8 g, 1.228 mmol) in methanol (10 mL) was added conc. hydrogenchloride (3.73 mL, 123 mmol), stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 24 g, eluting with 0-100% CMA-80in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140e) as a free base. To a solution of free base of compound 140e inmethanol (10 mL) was added conc. hydrochloric acid (0.121 mL, 1.450mmol), stirred for 30 mins and concentrated in vacuum to dryness toafford1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(m-tolyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(140e) (110 mg, 60.7% yield) hydrochloride salt as a white solid. ¹HNMR(300 MHz, DMSO-d₆) δ 10.82 (s, 1H, D₂O exchangeable), 10.12 (s, 2H, D₂Oexchangeable), 8.45 (s, 3H, D₂O exchangeable), 7.92 (dd, J=7.3, 2.3 Hz,1H), 7.76-7.66 (m, 3H), 7.63 (dt, J=7.3, 1.8 Hz, 1H), 7.57 (d, J=7.8 Hz,1H), 7.55-7.48 (m, 3H), 7.40 (dd, J=10.3, 8.6 Hz, 1H), 7.32 (t, J=7.9Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 5.59 (s, 1H), 4.13 (s, 2H), 2.69 (s,2H), 2.30 (s, 3H), 1.14 (dd, J=10.1, 5.5 Hz, 1H), 0.60-0.51 (m, 2H),0.29 (dd, J=5.8, 4.1 Hz, 2H). MS (ES+) 552.3 (M+1), (ES−) 550.2 (M−1),586.3 (M+35); Analysis calculated for C₃₀H₂₉F₄N₅O.2HCl.2H₂O: C, 56.14;H, 5.18; N, 10.91; Cl, 10.90; Found: C, 56.01; H, 5.27; N, 10.72; Cl,11.14.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141e) Step-1: Preparation of(3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a)

To a stirred solution of 3-methoxybenzaldehyde (109a) (1.825 mL, 15mmol) in tetrahydrofuran (15 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(18.0 mL, 18.0 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 2 N HCl (10 mL, 20 mmol), stirred for0.5 h. The reaction mixture was basified with saturated aqueous NaHCO₃and extracted with ethyl acetate (2×250 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL) dried over anhydrousMgSO₄, filtered, evaporated to dryness. The crude residue was purifiedby flash column chromatography (silica gel 80 g, eluting with 0-100%ethyl acetate in hexane) to furnish(3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a) (1.8 g, 7.28mmol, 48.5% yield) as a light brown oil; ¹HNMR (300 MHz, DMSO-d₆) δ 7.19(t, J=7.9 Hz, 1H), 6.93-6.87 (m, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.75 (ddd,J=8.5, 2.7, 1.2 Hz, 2H), 6.50 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.75 (d,J=3.9 Hz, 1H, D₂O exchangeable), 5.48 (d, J=3.9 Hz, 1H), 5.05 (s, 2H,D₂O exchangeable), 3.71 (s, 3H); Mass spec (ES+) 270.2 (M+23); (ES−)246.2 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.227 g, 7.92 mmol) in DMF (20 mL) was added(3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a) (1.78 g, 7.20mmol), N-ethyl-N-isopropylpropan-2-amine (6.27 mL, 36.0 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 4.03 g,8.64 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 20 h under nitrogen atmosphere. The reaction was dilutedwith water (100 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined, washed with water (2×100 mL), brine (50mL), dried, filtered, and evaporated in vacuum to dryness. The residueobtained was purified by flash column chromatography (silica gel 40 g,eluting with 0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141b) (2.105 g, 4.12 mmol, 57.3% yield) as a yellow semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.12 (t, J=1.8 Hz,1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (dt, J=8.4, 1.3 Hz, 1H),7.79-7.63 (m, 2H), 7.52 (d, J=7.2 Hz, 1H), 7.35-7.09 (m, 3H), 6.95-6.88(m, 2H), 6.83-6.68 (m, 1H), 6.00 (d, J=4.0 Hz, 1H, D₂O exchangeable),5.66 (d, J=3.9 Hz, 1H), 3.70 (s, 3H); MS (ES+) 533.2 (M+Na) (ES−) 509.2(M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141c)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141b) (2.05 g, 4.02 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.626 mL, 8.57 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was quenched with triethylamine (3.72 mL,26.7 mmol), stirred for 1 h, added cyclopropylmethanamine (1.52 mL,17.73 mmol) and concentrated in vacuum to remove dichloromethane. Thereaction mixture was diluted with acetonitrile (10 mL) and addedcyclopropylmethanamine (8.00 mL, 92 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in chloroform (300 mL),washed with water (100 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (silicagel 40 g, eluting with CMA 80 in chloroform (0 to 20%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141c) (0.838 g, 37.0% yield) as a off white semisolid; MS (ES+) 564.3(M+1) (ES−) 562.3 (M−1).

Step-4: Preparation of tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(141d)

To a solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141c) (0.8 g, 1.42 mmol) in MeOH (25 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (1.239 g, 5.68 mmol) and nickel(II)chloride (0.084 g, 0.355 mmol). Sodium borohydride (0.508 g, 14.20 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.690 mL, 6.39 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdiluted with water (200 mL). The solid obtained was collected byfiltration, dried in vacuum and purified by flash column chromatography(silica gel 40 g with 0-100% 9:1 ethyl acetate/methanol in hexane) toafford tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(141d) (0.35 g, 14.47% yield) as a white solid.

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141e)

To a solution of tert-butyl3-(5-((5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(141d) 0.69 g, 1.033 mmol) in methanol (10 mL) was added hydrogenchloride (3.14 mL, 103 mmol), stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with 0-100% CMA 80in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141e) free base as a white solid; To a solution of free base oftert-butyl3-(5-(5-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(141e) in methanol (10 mL) was added hydrochloric acid (10 eq) andstirred at room temperature for 30 mins and concentrated in vacuum todryness to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141e) (200 mgs) hydrochloride salt as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.79 (s, 1H, D₂O exchangeable), 10.09 (s, 2H, D₂Oexchangeable), 8.36 (d, J=16.1 Hz, 3H, D₂O exchangeable), 7.94 (s, 1H),7.75-7.48 (m, 6H), 7.36 (dt, J=16.4, 9.2 Hz, 3H), 7.21 (s, 1H), 6.92 (d,J=8.3 Hz, 1H), 5.58 (s, 1H), 4.13 (s, 2H), 3.75 (s, 3H), 2.68 (s, 2H),1.17-1.07 (m, 1H), 0.54 (d, J=7.5 Hz, 2H), 0.28 (s, 2H); MS (ES+) 568.3(M+1), 590.3 (M+23); (ES−) 566.3 (M−1), 602.3 (M+35); Analysiscalculated for C₃₀H₂₉F₄N₅O₂.3HCl.1.25H₂O: C, 51.60; H, 4.98; N, 10.03;Cl, 15.03; Found: C, 51.02; H, 4.85; N, 9.63; Cl, 15.63.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(141f) Step-1: Preparation of(3-amino-4-fluorophenyl)(4-methoxyphenyl)methanol (142b)

To a stirred solution of 4-anisaldehyde (142a) (1.825 mL, 15 mmol) intetrahydrofuran (15 mL) was added(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(20.25 mL, 20.25 mmol) at 0° C. The reaction was stirred for 14 h atsame temperature and quenched by adding 2 N HCl (10 mL, 20 mmol),stirred for 0.5 h. The reaction mixture was basified with saturatedaqueous NaHCO₃ and extracted with ethyl acetate (2×250 mL). The organiclayers were combined washed with water (2×50 mL), brine (50 mL) driedover anhydrous MgSO₄, filtered, evaporated to dryness. The crude residuewas purified by flash column chromatography (silica gel 80 g, elutingwith 0-100% ethyl acetate in hexane) to furnish(3-amino-4-fluorophenyl)(4-methoxyphenyl)methanol (142b) (2.125 g, 8.59mmol, 57.3% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 7.28-7.13 (m, 2H), 6.86 (dd, J=11.2, 8.4 Hz,3H), 6.74 (dd, J=9.1, 2.2 Hz, 1H), 6.47 (ddd, J=8.3, 4.5, 2.2 Hz, 1H),5.65 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.47 (d, J=3.9 Hz, 1H), 5.04(s, 2H, D₂O exchangeable), 3.71 (s, 3H).

MS (ES+) 270.2 (M+23); (ES−) 246.2 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.63 g, 9.34 mmol) in DMF (20 mL) was added(3-amino-4-fluorophenyl)(4-methoxyphenyl)methanol (142b) (2.1 g, 8.49mmol), N-ethyl-N-isopropylpropan-2-amine (7.40 mL, 42.5 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 4.75 g,10.19 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 20 h under nitrogen atmosphere. The reaction wasdiluted with water (100 mL) and extracted with ethyl acetate (2×100 mL).The organic layers were combined, washed with water (2×100 mL), brine(50 mL), dried, filtered, and evaporated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting with 0-100% ethyl acetate in hexanes) to furnish1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142c) (3.23 g, 6.33 mmol, 74.5% yield) as a yellow semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.12 (t, J=1.8 Hz,1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.92-7.86 (m, 1H), 7.76-7.69 (m, 2H),7.52-7.45 (m, 1H), 7.26-7.22 (m, 3H), 6.88-6.82 (m, 3H), 5.90 (d, J=4.0Hz, 1H, D₂O exchangeable), 5.64 (dd, J=4.0, 2.3 Hz, 1H), 3.71 (s, 3H);MS (ES+) 533.2 (M+Na), (ES−) 509.2 (M−1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142d)

To a solution of1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142c) (2.75 g, 5.39 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.840 mL, 11.50 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was quenched with triethylamine (0.771 mL,5.53 mmol), stirred for 1 h, added cyclopropylmethanamine (1.52 mL,17.73 mmol) and concentrated in vacuum to remove dichloromethane. Thereaction mixture was diluted with acetonitrile (10 mL) and addedcyclopropylmethanamine (1.520 mL, 17.73 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in chloroform (300 mL),washed with water (100 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (silicagel 40 g, eluting with CMA 80 in chloroform (0 to 20%) to afford1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142d) (1.448 g, 47.7% yield) as an white semisolid; MS (ES+) 564.3(M+1), (ES−) 562.3 (M−1).

Step-4: Preparation of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)(4-methoxyphenyl)methyl)(cyclopropylmethyl)carbamate(142e)

To a solution of1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142d) (1.4 g, 2.484 mmol) in MeOH (25 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (2.169 g, 9.94 mmol) and nickel(II)chloride (0.148 g, 0.621 mmol). Sodium borohydride (0.890 g, 24.84 mmol)was added slowly over 15 min and reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (1.208 mL, 11.18 mmol) stirred for0.5 h and concentrated in vacuum to dryness. The residue obtained wasdiluted with water (200 mL). The solid obtained was collected byfiltration, dried in vacuum and purified by flash column chromatography(silica gel 40 g with 0-100% 9:1 ethyl acetate/methanol in hexane) toafford tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)(4-methoxyphenyl)methyl)(cyclopropylmethyl)carbamate(142e) (0.906 g, 47.5% yield) as a white solid.

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142f)

To a solution of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)(4-methoxyphenyl)methyl)(cyclopropylmethyl)carbamate(142e) (0.88 g, 1.146 mmol) in methanol (5 mL) was added hydrogenchloride (3.48 mL, 115 mmol), stirred at room temperature overnight andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with 0-100% CMA 80in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142f) (0.487 g, 74%) free base as a white solid; To a solution of freebase of tert-butyl3-(5-(5-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(142f) (0.46 g, 0.81 mmol) in methanol (10 mL) was added hydrochloricacid (10 eq) and stirred at room temperature for 30 mins andconcentrated in vacuum to dryness to afford1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(142f) (80 mgs) hydrochloride salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.78 (s, 1H, D₂O exchangeable), 9.99 (s, 1H, D₂Oexchangeable), 8.45 (s, 2H, D₂O exchangeable), 7.85 (s, 1H), 7.71 (d,J=7.1 Hz, 2H), 7.57 (dq, J=17.6, 9.1, 8.4 Hz, 6H), 7.37 (t, J=9.6 Hz,1H), 6.96 (d, J=8.2 Hz, 2H), 5.48 (s, 1H), 4.12 (s, 2H), 3.74 (s, 3H),2.62 (s, 2H), 1.10 (s, 1H), 0.53 (d, J=7.8 Hz, 2H), 0.26 (s, 2H); Massspec (ES−) 566.3 (M−1), 602.2 (M+35); Analysis calculated forC₃₀H₂₉F₄N₅O₂.2HCl.2H₂O: C, 53.31; H, 5.22; N, 10.36; Cl, 10.35; Found:C, 53.53; H, 5.12; N, 10.11; Cl, 10.59.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (143l) Step-1: Preparation of4-Methoxyimino-2-oxo-pentaneperoxoic acid ethyl ester (143c) and2-Methoxyimino-4-oxo-pentaneperoxoic Acid Ethyl Ester (143d)

To a suspension of 2,4-Dioxo-pentanoic acid ethyl ester (143b) (25 g,158.07 mmol) in ethanol (325 mL) was added methoxylaminehydrochloride(13.86 g, 165.97 mmol) and Molecular sieves (125 gm). The reactionmixture was stirred at room temperature overnight and filtered throughhyflow bed. The reaction mixture was concentrated in vacuum and theresidue obtained was dissolved in diethyl ether (600 mL). The organiclayer was washed with brine (300 mL), dried, filtered and concentratedin vacuum to afford crude product. The crude was purified by flashcolumn chromatography (silica gel 400 g, eluting with 0-20% ethylacetate in hexane) to furnish:

-   -   1. 2-Methoxyimino-4-oxo-pentaneperoxoic acid ethyl ester (143d)        (8 g, 27%); ¹H NMR (300 MHz, DMSO-d₆) δ 4.28-4.16 (m, 2H), 3.96        (s, 3H), 3.65 (s, 2H), 1.76 (d, J=1.4 Hz, 3H), 1.30-1.16 (m,        3H).    -   2. 4-Methoxyimino-2-oxo-pentaneperoxoic acid ethyl ester (143c)        (12 g, 41%); ¹H NMR (300 MHz, DMSO-d₆) δ 4.20 (q, J=7.1 Hz, 2H),        3.95 (s, 3H), 3.71 (s, 2H), 2.15 (s, 3H), 1.23 (t, J=7.1 Hz,        3H).

Step-2: Preparation of 3-hydrazinylbenzonitrile Hydrochloride (143a)

To 3-Amino-benzonitrile (10a) (34 g, 287.79 mmol) at 0° C. was addedslowly dropwise HCl (136 mL). To this was added a pre-dissolved solutionof Sodium nitrite (25.81 g, 374.13 mmol) in 50 mL H₂O drop wise at arate so as to maintain internal temperature between 0 to 5° C. Thereaction was stirred for 1 hour at 0° C. followed by the dropwiseaddition of a freshly prepared solution of stannous chloride dihydrate(142.8 g, 633.147 mmol) in conc. HCl (95.2 mL) maintaining internaltemperature between 0 to 10° C. The reaction mixture was allowed to warmto room temperature and stirred for 2 h. The crude3-hydrazinylbenzonitrile Hydrochloride (143a) obtained as a creamishcolored liquid was used directly as such for next step.

Step-3: Preparation of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic Acid Ethyl Ester(143e)

To a suspension of 4-Methoxyimino-2-oxo-pentaneperoxoic acid ethyl ester(143c) (12 g, 64.11 mmol) in ethanol (120 mL) was added3-Hydrazino-benzonitrile hydrochloride salt prepared in step-2 (288 mL)with stirring. The reaction mixture was heated at reflux overnight.Progress of reaction was checked by TLC (EtOAc/n-Hex=2:8). Aftercompletion of reaction the reaction mixture was concentrated in vacuumto remove ethanol. The residue obtained was solvent was extracted withethyl acetate (200×3). The organic layers were combined washed withbrine (300 mL), dried, filtered and concentrated in vacuum to affordcrude product. The crude was purified by flash column chromatography(silica gel 250 g, eluting with 0-16% ethyl acetate in hexane) tofurnish 2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethylester (143e) (9 g, 55%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.06-8.03 (m, 1H),7.92 (dt, J=7.7, 1.4 Hz, 1H), 7.83 (ddd, J=8.2, 2.2, 1.2 Hz, 1H),7.73-7.64 (m, 1H), 6.96 (d, J=0.6 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.28(s, 3H), 1.17 (t, J=7.1 Hz, 3H).

Step-4: Preparation of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic Acid (143f)

To a suspension of 2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylicacid ethyl ester (143e) (8.5 g, 33.3 mmol) in MeOH/THF (⅓, 21+63 mL) wasadded 3 N NaOH (4 g, 100 mmol) with stirring. The reaction mixture wasstirred for 2 h (Progress of reaction was checked by TLC(MeOH/CHCl_(3=1/9)). The reaction mixture was concentrated in vacuum toremove THF and methanol. The aqueous layer was acidified using conc. HClat 5-15° C. temperature and extracted with ethyl acetate (3×100). Theorganic layers were combined washed with brine (300 mL), dried, filteredand concentrated in vacuum to afford crude2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143f) (6.7 g,89%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (t, J=1.9 Hz, 1H), 7.89 (dt,J=7.7, 1.4 Hz, 1H), 7.81 (ddd, J=8.2, 2.2, 1.2 Hz, 1H), 7.66 (t, J=7.9Hz, 1H), 6.88 (s, 1H), 2.27 (s, 3H).

Step-5: Preparation of (3-Amino-phenyl)-phenyl-methanol (143h)

To a stirred solution of (3-aminophenyl)(phenyl)methanone (143g) (0.97g, 4.89 mmol) in methanol (25 mL), cooled to 0° C., were added,nickel(II) chloride hexahydrate (0.29 g, 1.22 mmol), followed by portionwise addition of sodium borohydride (1.11 g, 29.4 mmol) over 45 min. Thereaction mixture was stirred for 15 min at room temperature and quenchedwith N1-(2-aminoethyl)ethane-1,2-diamine (1.057 mL, 9.79 mmol. Thereaction mixture was stirred for 30 minutes and concentrated in vacuumto dryness. The residue was treated with water (25 mL) extracted withethyl acetate (2×25 mL). The organic layers were combined washed withbrine (25 mL), dried filtered and concentrated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography [(silicagel 25 g, eluting with ethyl acetate/hexanes from 0 to 100%)] to furnish(3-Amino-phenyl)-phenyl-methanol (143h) (772 mg, 3.87 mmol, 79% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.36-7.24 (m, 4H),7.21-7.14 (m, 1H), 6.91 (t, J=7.7 Hz, 1H), 6.57 (t, J=2.0 Hz, 1H), 6.51(dt, J=7.5, 1.3 Hz, 1H), 6.37 (ddd, J=8.0, 2.4, 1.1 Hz, 1H), 5.69 (d,J=3.8 Hz, 1H), 5.50 (d, J=3.8 Hz, 1H), 4.99 (s, 2H); MS (ES+) 222.1(M+1), (ES−) 198.0 (M−1).

Step-6: Preparation of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenyl-methyl)-phenyl]-amide (143i)

To a stirred solution of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143f) (2.5 g,11.002 mmol) in DMF (50 mL) was added (3-Amino-phenyl)-phenyl-methanol(143h) (2.19 g, 11.00 mmol), DIPEA (11.38 g, 88.02 mmol) and PyBrop(5.13 g, 11.00 mmol). The reaction mixture was stirred at roomtemperature overnight. Progress of reaction was checked by TLC(EtOAc/n-Hex=4:6). After completion of reaction the reaction, themixture was diluted with water (200 mL) and extracted with ethyl acetate(3×200 mL). The organic layers were combined washed with water (2×200mL), brine (200 mL), dried, filtered and concentrated in vacuum toafford crude product. The crude was purified by flash columnchromatography (silica gel 100 g, eluting with 15-35% ethyl acetate inhexane) to furnish 2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylicacid [3-(hydroxy-phenyl-methyl)-phenyl]-amide (143i) (0.55 gm), whichwas used as such for next step.

Step-7: Preparation of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenyl-methyl]-phenyl}-amide (143j)

To an ice cold solution of2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenyl-methyl)-phenyl]-amide (143i) (0.5 g, 1.22 mmol) inacetonitrile (10 mL) was added dropwise thionyl chloride (0.29 g, 2.45mmol) maintaining internal temperature between 5-10° C. The reactionmixture was allowed to warm to room temperature over a period of 3.5 h.The reaction mixture was concentrated in vacuum to dryness and to theresidue was added acetonitrile (5 mL), cyclopropyl methylamine (1.31 g,18.36 mmol). The reaction mixture was heated at reflux overnight thereaction mass for overnight. Progress of reaction was checked by TLC(EtOAc/n-Hex=4:6). The reaction mixture on completion was concentratedin vacuum to dryness. To the residue was added water (50 mL) andextracted with ethyl acetate (3×50 mL). The organic layers were combinedwashed with brine (50 mL), dried, filtered and concentrated in vacuum toafford crude product. The crude was purified by flash columnchromatography (silica gel 40 g, eluting with 20-45% ethyl acetate inhexane) to furnish 2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylicacid {3-[(cyclopropylmethyl-amino)-phenyl-methyl]-phenyl}-amide (143j)(0.4 g, 71%); ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.95 (t, J=1.9Hz, 1H), 7.87 (dq, J=2.4, 1.5, 1.1 Hz, 1H), 7.85-7.80 (m, 1H), 7.78-7.73(m, 1H), 7.72-7.66 (m, 2H), 7.66-7.60 (m, 1H), 7.53 (d, J=8.0 Hz, 1H),7.41 (d, J=1.7 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J=7.2 Hz, 2H), 7.21-7.17(m, 2H), 6.98 (s, 1H), 6.67 (s, 1H), 3.45 (dd, J=12.8, 6.3 Hz, 2H),1.87-1.82 (m, 3H), 0.91-0.77 (m, 1H), 0.46-0.25 (m, 2H), 0.11-−0.05 (m,2H).

Step-8: Preparation of[3-(5-{3-[(Cyclopropylmethyl-amino)-phenyl-methyl]-phenylcarbamoyl}-3-methyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (143k)

To a solution of 2-(3-Cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylicacid {3-[(cyclopropylmethyl-amino)-phenyl-methyl]-phenyl}-amide (143j)(0.36 g, 0.78 mmol) in MeOH (10 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (0.22 g, 0.94 mmol) and Boc anhydride(0.51 g, 2.34 mmol) followed by portionwise addition of sodiumborohydride (0.17 g, 4.67 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 0.5 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.17 mL, 1.56 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting with 30-45% Ethyl acetate/hexane) to furnish[3-(5-{3-[(Cyclopropylmethyl-amino)-phenyl-methyl]-phenylcarbamoyl}-3-methyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (143k) (0.19 g, 43%); ¹H NMR (300 MHz, DMSO-d₆) δ10.46 (s, 1H), 7.67 (s, 1H), 7.55-7.10 (m, 12H), 6.83 (s, 1H), 4.80 (s,1H), 4.15 (d, J=6.2 Hz, 2H), 3.23 (d, J=6.5 Hz, 2H), 2.26 (s, 3H), 1.39(d, J=1.7 Hz, 9H), 0.99-0.87 (m, 1H), 0.38 (dt, J=8.1, 2.9 Hz, 2H), 0.04(q, J=4.8 Hz, 2H).

Step-9: Preparation of2-(3-Aminomethyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid{3-[(cyclopropylmethyl-amino)-phenyl-methyl]-phenyl}-amide (143l)

To a solution of[3-(5-{3-[(Cyclopropylmethyl-amino)-phenyl-methyl]-phenylcarbamoyl}-3-methyl-pyrazol-1-yl)-benzyl]-carbamicacid tert-butyl ester (143k) (0.18 g, 0.32 mmol) in methanol (10 mL) andadded conc. HCl (1 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuum to dryness. The residuewas azeotroped with toluene (2×10 mL) and ethanol (10 mL), dried invacuum pump to furnish a residue. The residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-6% methanol indichloromethane to furnish (0.08 g, 54%) as a yellow solid. This wasagain repurified by flash column chromatography (silica gel 12 g,eluting with 0-100% cma-80 in chloroform) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide(143l) (10.74 μmol, 6.67% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.46 (s, 1H), 7.69 (s, 1H), 7.50 (d, J=7.9 Hz, 1H),7.45-7.42 (m, 1H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.29-7.24 (m,1H), 7.23-7.14 (m, 4H), 6.83 (s, 1H), 4.80 (s, 1H), 3.76 (s, 2H), 2.29(s, 3H), 2.27 (d, J=2.9 Hz, 2H), 1.00-0.88 (m, 1H), 0.44-0.30 (m, 2H),0.08-0.01 (m, 2H); MS (ES+) 466.4 (M+1); (ES−) 464.4 (M−1); 500.3(M+Cl).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((isopropylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144d) Step-1: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid[3-(hydroxyphenylmethyl)phenyl]amide (144a)

In a 100 mL single-necked flask1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.682 g, 2.427 mmol), 3-aminophenyl)(phenyl)methanol (143h) (0.403 g,2.023 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop, 1.131 g, 2.427 mmol) was addedN,N-dimethylformamide (DMF, 12 mL) and N-ethyl-N-isopropylpropan-2-amine(DIPEA, 1.762 mL, 10.11 mmol) successively in a positive flow ofnitrogen at room temperature. The resulting reaction mixture was stirredat room temperature for 16 h under a positive flow of nitrogenatmosphere. Excess DMF was pumped-off under reduced pressure. Theresidue was treated with water (30 mL) and extracted with ethyl acetate(2×30 mL). The organic layers were combined, washed with water (30 mL),brine (30 mL), dried over anhydrous MgSO₄, filtered and concentrated invacuum to dryness. The residue was purified by flash columnchromatography [silica gel 40 g, eluting with methanol in chloroformfrom 0-80%] to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (0.853 g, 1.845 mmol, 91% yield) as a white solid; 1H NMR (300MHz, DMSO-d₆) δ 10.64 (s, 1H, D₂O exchangeable), 8.16 (t, J=1.8 Hz, 1H),8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H),7.78-7.69 (m, 2H), 7.64 (t, J=1.8 Hz, 1H), 7.55 (dt, J=8.1, 1.5 Hz, 1H),7.38-7.31 (m, 3H), 7.30 (t, J=1.3 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H),7.25-7.17 (m, 1H), 7.16-7.12 (m, 1H), 5.95 (d, J=3.8 Hz, 1H, D₂Oexchangeable), 5.67 (d, J=3.8 Hz, 1H); 19F NMR (282 MHz, DMSO d₆) δ−60.96; MS (ES+) 485.2 (M+Na), MS (ES−) 590.3923 (M+Cl), 959.2 (2M−1).

Step-2: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid[3-(isopropylamino-phenyl-methyl)-phenyl]-amide (144b)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxyphenylmethyl)phenyl]amide (144a) (1.0 g, 2.162 mmol) indichloromethane (50 mL) at 0° C. was added thionyl chloride (0.514 g,4.325 mmol) and stirred at room temperature for 3 h. Isopropylamine(0.638 g, 10.81 mmol) was added and stirred for 30 min. The reactionmixture was concentrated in vacuum to dryness. The residue obtained wasdissolved in acetonitrile (20 mL) and added Isopropylamine (0.638 g,10.81 mmol)). The reaction mixture was heated at reflux overnight,cooled to room temperature and concentrated in vacuum to dryness. Theresidue was dissolved in dichloromethane (20 mL), washed with water(2×25 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel 40 g,eluting 0-25% ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(isopropylamino-phenyl-methyl)-phenyl]-amide (144b) (0.65 g, 60%) ascolorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.15 (t,J=1.9 Hz, 1H), 7.99 (dt, J=7.8, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.54 (dt,J=7.9, 1.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.28 (dd, J=8.2, 6.6 Hz, 2H),7.24-7.14 (m, 3H), 4.91 (s, 1H), 2.59-2.52 (m, 1H), 1.01 (d, J=6.2 Hz,6H); MS (ES−) 502.3 (M−1).

Step-3: Preparation of(3-{5-[3-(Isopropylamino-phenyl-methyl)-phenylcarbamoyl]-3-trifluoromethyl-pyrazol-1-yl}-benzyl)-carbamicAcid Tert-Butyl Ester (144c)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(isopropylamino-phenyl-methyl)-phenyl]-amide (144b) (0.6 g, 1.19mmol) in MeOH (15 mL) cooled with ice/water was added nickel(II)chloride hexahydrate (0.35 g, 1.49 mmol) and Boc anhydride (0.779 g,3.57 mmol) followed by portion-wise addition of Sodium Borohydride (0.27g, 7.15 mmol) over a period of 5 min. The reaction mixture was stirredat room temperature for 2 h and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.49 g, 4.764 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish(3-{5-[3-(Isopropylamino-phenyl-methyl)-phenylcarbamoyl]-3-trifluoromethyl-pyrazol-1-yl}-benzyl)-carbamicacid tert-butyl ester (144c) (0.420 gm) as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.69-7.16 (m, 14H), 4.19 (d, J=6.2Hz, 1H), 1.36 (s, 9H), 1.21-1.09 (m, 6H); MS (ES−) 606.3 (M−1).

Step-4: Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic Acid[3-(isopropylamino-phenyl-methyl)-phenyl]-amide (114d)

To a solution of(3-{5-[3-(Isopropylamino-phenyl-methyl)-phenylcarbamoyl]-3-trifluoromethyl-pyrazol-1-yl}-benzyl)-carbamicacid tert-butyl ester (144c) (0.4 gm 1.65 mmol) in MeOH (10 mL) wasadded conc. HCl (0.5 mL). The reaction mixture was stirred at roomtemperature for 19 h. The reaction mass was concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-15% MeOH/DCM) to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(isopropylamino-phenyl-methyl)-phenyl]-amide (0.250g, 30%) as ayellowish solid. This was repurified by flash column chromatography(silica gel 12 g, eluting with 0-100% CMA-80 in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((isopropylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144d) (0.092 g, 36.8% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.98 (s, 1H), 9.80 (s, 2H), 8.50 (s, 3H), 7.98-7.92 (m, 1H),7.81-7.75 (m, 2H), 7.74-7.70 (m, 3H), 7.66-7.36 (m, 7H), 5.65 (s, 1H),4.12 (s, 2H), 3.03 (s, 1H), 1.43-1.21 (m, 7H); ¹⁹F NMR (282 MHz, DMSO) δ−60.78; MS (ES+) 508.3 (M+1); 530.3 (M+Na); (ES−) 506.3 (M−1); 542.3(M+Cl); Analysis calculated for C₂₈H₂₈F₃N₅O.1.95HCl.2.25H₂O: C, 54.31;H, 5.61; Cl, 11.17; N, 11.31; Found: C, 54.55; H, 5.37; Cl, 10.98; N,11.00.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((2-hydroxyethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(145c) Step-1: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylicAcid{3-[(2-hydroxy-ethylamino)-phenyl-methyl]-phenyl}-amide (145a)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxyphenylmethyl)phenyl]amide (144a) (1.0 g, 2.162 mmol) indichloromethane (50 mL) at 0° C. was added thionyl chloride (0.514 g,4.325 mmol) and stirred at room temperature for 3 h. 2-Amino-ethanol(0.660 gm, 10.81 mmol) was added and stirred for 30 min. The reactionmixture was concentrated in vacuum to dryness. The residue obtained wasdissolved in acetonitrile (20 mL) and added 2-Amino-ethanol (0.660 gm,10.81 mmol). The reaction mixture was heated at reflux overnight, cooledto room temperature and concentrated in vacuum to dryness. The residuewas dissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-hydroxy-ethylamino)-phenyl-methyl]-phenyl}-amide (145a) (0.75 g,69%) as a colorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H),8.18-8.11 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz, 1H), 7.89 (ddd, J=8.1, 2.2,1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.54(dd, J=8.0, 1.9 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.33-7.23 (m, 3H),7.22-7.18 (m, 2H), 4.79 (d, J=4.6 Hz, 1H), 4.56 (t, J=5.4 Hz, 1H),3.85-3.68 (m, 1H), 3.54-3.49 (m, 2H); MS (ES−) 504.3 (M−1).

Step-2: Preparation of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl)(2-hydroxyethyl)carbamate(145b)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-hydroxy-ethylamino)-phenyl-methyl]-phenyl}-amide (145b) (0.7 g,1.38 mmol) in MeOH (15 mL) cooled with ice/water was added nickel(II)chloride hexahydrate (0.41 g, 1.73 mmol) and Boc anhydride (0.91 g, 4.15mmol) followed by portion-wise addition of Sodium Borohydride (0.31 g,8.30 mmol) over a period of 5 min. The reaction mixture was stirred atroom temperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.57 g, 5.54 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl)(2-hydroxyethyl)carbamate(145b) (0.35 g, 36%) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.75(s, 1H), 7.72-7.66 (m, 1H), 7.57 (s, 1H), 7.50 (t, J=6.3 Hz, 1H),7.44-7.39 (m, 3H), 7.38-7.34 (m, 3H), 7.32 (d, J=7.5 Hz, 3H), 7.18-7.11(m, 2H), 6.93-6.87 (m, 1H), 6.29 (s, 1H), 4.46 (t, J=5.3 Hz, 1H), 4.19(d, J=6.2 Hz, 2H), 3.31-3.10 (m, 2H), 3.09-2.83 (m, 2H), 1.32 (s, 18H);MS (ES−) 708.3 (M−1).

Step-3 Preparation of2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-hydroxy-ethylamino)-phenyl-methyl]-phenyl}-amide (145c)

To a solution of tert-butyl((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl)(2-hydroxyethyl)carbamate(145b) (0.32 gm 0.45 mmol) in MeOH (10 mL) was added conc. HCl (0.4 mL).The reaction mixture was stirred at room temperature for 19 hrs. Thereaction mass was concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 24 g, eluting with0-15% MeOH/DCM) to furnish2-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-hydroxy-ethylamino)-phenyl-methyl]-phenyl}-amide (145c) (0.06 g,26%) as a yellowish solid. The product were repurified by flash columnchromatography (silica gel 12 g, eluting with 0-100% cma-80 inchloroform) to afford pure (145c) (0.02 gm) as an off white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.97 (s, 2H), 8.41 (s, 3H), 7.85(s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.70-7.48 (m, 7H), 7.47-7.33 (m, 4H),5.62 (s, 1H), 5.24 (s, 1H), 4.13 (s, 2H), 3.71 (d, J=5.5 Hz, 2H), 2.89(s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+) 510.3 (M+1); (ES−)508.3 (M−1); 544.2 (M+Cl).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,5-dihydroxyphenyl)methyl) phenyl)-3-methyl-1H-pyrazole-5-carboxamide(146g) Step-1: Preparation of(3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (146b)

To a stirred solution of 2,5-bis(benzyloxy)benzaldehyde (146a) (3.2 g,10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith sat. NH₄Cl (50 mL), dried over anhydrous MgSO₄, filtered,evaporated to dryness. The crude residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-aminophenyl)(2,5-bis(benzyloxy)phenyl)methanol(146b) (2.4 g, 58.32%) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.46-7.29 (m, 10H), 7.14 (d, J=3.1 Hz, 1H), 6.94-6.84 (m, 2H), 6.80(dd, J=8.9, 3.1 Hz, 1H), 6.57 (t, J=1.9 Hz, 1H), 6.50-6.44 (m, 1H), 6.38(ddd, J=8.0, 2.3, 1.0 Hz, 1H), 5.86 (d, J=4.4 Hz, 1H), 5.52 (d, J=4.4Hz, 1H), 5.01 (d, J=1.2 Hz, 4H), 4.93 (s, 2H).

Step-2: Preparation ofN-(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.57 g, 5.589 mmol) in DMF (40 mL) was added(3-aminophenyl)(2,5-bis(benzyloxy)phenyl)methanol (146b) (2.3 gm, 5.589mmol), N-ethyl-N-isopropylpropan-2-amine (5.8 g, 44.93 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop2.6 g,5.589 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 42 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (350 mL) washed with water (2×150 mL), brine(120 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-30%] to furnishN-(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146c) (2.55 g, 67.62%) as a off white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.61 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.8, 1.3 Hz, 1H),7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75-7.66 (m, 2H), 7.64 (d, J=1.9Hz, 1H), 7.56-7.49 (m, 1H), 7.45-7.27 (m, 10H), 7.21 (t, J=7.8 Hz, 1H),7.13 (d, J=3.1 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H),6.82 (dd, J=8.9, 3.1 Hz, 1H), 5.96 (d, J=4.3 Hz, 1H), 5.79 (d, J=4.3 Hz,1H), 5.00 (d, J=1.9 Hz, 4H).

Step-3: Preparation ofN-(3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146d)

To a solution ofN-(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146c) (2.5 gm, 3.705 mmol) in dichloromethane (50 mL) at 0° C. wasadded thionyl chloride (0.53 g, 7.41 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated in vacuum todryness. The residue obtained was dissolved in acetonitrile (40 mL) andadded cyclopropylmethanamine (4.826 g, 55.57 mmol). The reaction mixturewas heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (50 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-40% ethyl acetate inhexane) to affordN-(3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146d) (0.9 gm, 33.37%) as brown sticky liquid; ¹HNMR (300 MHz, DMSO-d₆)δ 10.60 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 7.95 (dt, J=7.7, 1.3 Hz, 1H),7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.69 (s, 1H), 7.66 (d, J=2.4 Hz,1H), 7.54-7.48 (m, 1H), 7.46-7.24 (m, 11H), 7.21 (t, J=7.8 Hz, 1H), 7.13(d, J=3.1 Hz, 1H), 7.08 (dt, J=7.8, 1.3 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H),6.80 (dd, J=8.9, 3.1 Hz, 1H), 5.17 (s, 1H), 5.00 (d, J=3.3 Hz, 4H), 2.24(qd, J=12.0, 6.7 Hz, 2H), 1.86 (dt, J=4.9, 2.4 Hz, 1H), 0.93-0.74 (m,1H), 0.38-0.27 (m, 2H), 0.09-−0.20 (m, 2H).

Step-4: tert-butyl3-(5-((3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(146f)

To a solution ofN-(3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146d) (0.9 gm, 1.236 mmol) in MeOH (12 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.367 g, 1.548 mmol) and Bocanhydride (0.809 g, 3.708 mmol) followed by portionwise addition ofsodium borohydride (0.280 g, 7.416 mmol) over a period of 15 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N¹-(2-aminoethyl)ethane-1,2-diamine (0.510 mL, 4.944 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness and the residue obtained was dissolved inchloroform (25 mL) and water (25 mL). The aqueous layer was separatedextracted with chloroform (25 mL). The combined extracts were washedwith brine (25 mL), dried over MgSO₄ filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish

-   -   1. tert-butyl        ((2,5-bis(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)        phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)        methyl)(cyclopropylmethyl)carbamate (146e) (0.08 g, 6.94%)¹H NMR        (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.65 (s, 2H), 7.56 (s, 1H),        7.51-7.24 (m, 17H), 7.10-6.83 (m, 2H), 6.63-6.47 (m, 2H), 5.02        (t, J=11.7 Hz, 4H), 4.18 (d, J=5.1 Hz, 2H), 3.23-2.82 (m, 1H),        1.37 (s, 18H), 0.93-0.82 (m, 1H), 0.23-0.04 (m, 2H), −0.13-−0.42        (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.65; MS (ES+) 954.5        (M+Na); (ES−) 930.5 (M−1).    -   2. tert-butyl        3-(5-((3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)        methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (146f) (0.12 g, 0.12 g, 11.67%)¹H NMR (300 MHz, DMSO-d₆) δ 10.66        (s, 1H), 7.63 (s, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.49 (t, J=8.1        Hz, 1H), 7.34 (dtq, J=11.8, 9.6, 4.8 Hz, 13H), 7.20 (t, J=7.8        Hz, 1H), 7.15-6.75 (m, 2H), 5.01 (d, J=4.7 Hz, 2H), 4.17 (d,        J=6.0 Hz, 2H), 1.36 (d, J=4.1 Hz, 9H), 1.23-1.13 (m, 1H), 0.85        (s, 2H), 0.36 (dd, J=21.4, 8.4 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO)        δ −60.784; MS (ES+) 832.5 (M+1); (ES) 830.4 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,5-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (146g)

To a solution of tert-butyl3-(5-(3-((2,5-bis(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(146f) (0.12 g, 0.144 mmol) in dichloromethane (10 mL) cooled to 0° C.was added dropwise under a nitrogen atmosphere tribromoborane (1 Msolution in dichloromethane) (0.577 mL, 0.577 mmol). The reactionmixture was allowed to warm to room temperature and stirred at roomtemperature 2 h. The reaction mixture was quenched with methanol (5 mL)and concentrated in vacuo to dryness. The residue obtained wastriturated with methanol and dried under vacuum, this step was repeatedfour times to furnish crude product. The residue obtained was purifiedtwice by flash column chromatography [silica gel 12 g and 4 g, elutingwith CMA-80 in chloroform from 0-100%] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,5-dihydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(146g) (0.045 g, 56.6%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.74 (s, 1H), 8.63 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.59-7.50 (m, 3H),7.46-7.40 (m, 2H), 7.32 (dd, J=6.4, 2.7 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H),7.23-7.16 (m, 1H), 6.50 (d, J=8.3 Hz, 1H), 6.47-6.40 (m, 2H), 4.91 (s,1H), 3.78 (s, 2H), 2.43-2.18 (m, 2H), 0.94 (m, 1H), 0.40 (m, 2H), 0.08(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.70; MS (ES+) 552.3 (M+1); (ES−)550.3 (M+1); Analysis calculated for C₂₉H₃₁N₅O₃-0.75HBr: C, 62.39; H,5.73; N, 12.54; Found: C, 62.23; H, 5.44; N, 12.16.

Preparation ofN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147e) Step-1: Preparation ofN-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b)

To a stirred solution of N-(4-formylphenyl)acetamide (147a) (3.26 g, 20mmol) in tetrahydrofuran (30 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24 mL,24.00 mmol) at 0° C. The reaction was stirred for 14 h at sametemperature and quenched by adding 12 N HCl (4.17 mL, 50.0 mmol),stirred for 1 h. The reaction mixture was treated with 2 N NaOH (30.0mL, 60.0 mmol) and extracted with ethyl acetate (2×50 mL). The organiclayers were combined washed with sat. NH₄Cl (50 mL), dried overanhydrous MgSO₄, filtered, evaporated to dryness. The crude residue waspurified by flash column chromatography (silica gel 120 g, eluting with0-100% ethyl acetate in hexane) to furnishN-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b) (2.098 g,41% yield) as a yellow solid which was used as such in the next step; MS(ES−): 255.2 (M−1).

Step-2: Preparation ofN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147c)

A single-necked 100 mL flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.61 g, 9.28 mmol),N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b) (1.983 g,7.74 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 4.33 g, 9.28 mmol) was addedN,N-dimethylformamide (44.9 mL, 580 mmol) andN-ethyl-N-isopropylpropan-2-amine (6.74 mL, 38.7 mmol) successively in apositive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. Excess DMF was pumped-off under reducedpressure. The residue was treated with water (250 mL), and extractedwith chloroform (2×250 mL) combined organics were dried over anhydrousMgSO₄, filtered, evaporated to dryness. The residue was then purified byflash column chromatography [silica gel 40 g, eluting with methanol inchloroform from 0-100%] to furnishN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147c) (1.159 g, 29% yield) as a yellow solid; MS (ES−): 518.2 (M−1).

Step-3: Preparation ofN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147d)

To a solution ofN-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147c) (1.139 g, 2.193 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.480 mL, 6.58 mmol), reaction mixture allowedto warm to room temperature and stirred for 3 h. The reaction mixturewas quenched with triethylamine (1.528 mL, 10.96 mmol), and solution wasstirred for 30 min at room temperature, and concentrated in vacuum todryness. The residue was dissolved in acetonitrile (20 mL) to this wascyclopropylmethanol (18.64 mL, 254 mmol) and triethylamine (1.528 mL,10.96 mmol) were added and stirred at 100° C. for 18 h. The reactionmixture was cooled to room temperature evaporated under reducedpressure. The residue was purified by flash column chromatography(silica gel 40 g, eluting with methanol in chloroform from 0-100%) toaffordN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147d) (0.494 g, 39% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.67 (s, 1H), 9.92 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.8,1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78-7.70 (m, 2H), 7.59(t, J=3.3 Hz, 2H), 7.54-7.47 (m, 2H), 7.35-7.20 (m, 3H), 7.11 (d, J=7.7Hz, 1H), 5.38 (s, 1H), 3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1.04 (d,J=5.2 Hz, 1H), 0.49-0.42 (m, 2H), 0.17-0.12 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.93; MS (ES⁺): MS (ES+) 574.4 (M+1), 596.4 (M+Na), MS(ES−) 572.2 (M−1).

Step-4: Preparation ofN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147e)

To a stirred solution ofN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147d) (0.481 g, 0.839 mmol) in anhydrous methanol (10 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.100 g, 0.419 mmol),sodium borohydride (0.254 g, 6.71 mmol) was then added in small portionsover 5 min. The reaction was exothermic and effervescent. The reactionmixture was stirred for 15 min at 0° C., at this pointN1-(2-aminoethyl)ethane-1,2-diamine (0.906 mL, 8.39 mmol) was added. Themixture was allowed to stir for 30 minutes more before solvent wasevaporated. The residue was treated with water (30 mL), and extractedwith chloroform (2×30 mL), then ethyl acetate (2×30 mL), combinedorganic layers were dried over anhydrous MgSO₄, and filtered, excesssolvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography [(silica gel 40 g, eluting withCMA80/chloroform from 0 to 100%)] to furnishN-(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(147e) (203 mg, 42% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H,), 9.93 (s, 1H, D₂O exchangeable), 7.62-7.48 (m,6H), 7.47-7.41 (m, 2H), 7.36-7.20 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 5.37(s, 1H), 3.79 (s, 2H), 3.21 (dd, J=6.8, 1.3 Hz, 2H), 2.01 (s, 3H), 1.04(ddd, J=12.7, 8.5, 5.3 Hz, 1H), 0.55-0.38 (m, 2H), 0.14 (tq, J=4.5, 2.3,1.9 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 7.62-7.41 (m, 8H),7.37-7.21 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 5.37 (s, 1H), 3.78 (s, 2H),3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1.13-0.96 (m, 1H), 0.46 (dd,J=7.6, 2.3 Hz, 2H), 0.13 (dd, J=4.5, 2.3 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.71; MS (ES+): MS (ES+) 578.3 (M+1), MS (ES−) 612.3(M+Cl); Analysis calculated for: C₃₁H₃₀F₃N₅O₃: C, 64.46; H, 5.24; N,12.12; Found: C, 64.03; H, 5.24; N, 11.77.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(148b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(148a)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[hydroxy-(2-methoxy-naphthalen-1-yl)-methyl]-phenyl}-amide (51c) (3.5g, 6.45 mmol) in dichloromethane (50 mL) at 0° C. was added thionylchloride (1.413 mL, 19.35 mmol) and stirred at room temperature for 2 h.The reaction was treated with triethylamine (5.40 mL, 38.7 mmol) andstirred at room temperature for 8 h. The reaction was treated withcyclopropanemethanol (10.22 mL, 129 mmol), concentrated to remove mostof dichloromethane followed by addition of acetonitrile (50.0 mL) andheating at reflux for 16 h. Reaction was concentrated to dryness,diluted water (200 mL) and extracted with ethylacetate (3×300 mL). Theorganic layers were combined washed with water (100 mL), brine (100 mL)dried over MgSO₄ followed by filtration and concentration. Residue waspurified by flash column chromatography (silica gel, 120 g eluting withethyl acetate in hexanes 0 to 30%) to afford pure1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(145a) (2.5 g, 65.0% yield) as a white solid.

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(148b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(145a) (1.862 g, 3.12 mmol) in methanol (70 mL) at 0° C. was addednickel(II) chloride hexahydrate (0.162 g, 0.680 mmol). To this sodiumtetrahydroborate (1.181 g, 31.2 mmol) was added in small portions over aperiod of 10 minutes. The reaction was stirred for 1 h, quenched byadding N1-(2-aminoethyl)ethane-1,2-diamine (0.805 g, 7.80 mmol) andstirred for 1 h. The reaction mixture was concentrated to removemethanol, diluted with water (150 mL) and stirred for 30 minutes. Thesolid separated was collected by filtration, dried in vacuum andpurified by flash column chromatography (silica gel, 40 g eluting withethyl acetate in hexanes 0 to 100%) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(148b) (0.91 g, 48.5% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H,), 9.93 (s, 1H, D₂O exchangeable), 7.62-7.48 (m,6H), 7.47-7.41 (m, 2H), 7.36-7.20 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 5.37(s, 1H), 3.79 (s, 2H), 3.21 (dd, J=6.8, 1.3 Hz, 2H), 2.01 (s, 3H), 1.04(ddd, J=12.7, 8.5, 5.3 Hz, 1H), 0.55-0.38 (m, 2H), 0.14 (tq, J=4.5, 2.3,1.9 Hz, 2H); 1H NMR (300 MHz, DMSO-d₆, D₂O) δ 7.62-7.41 (m, 8H),7.37-7.21 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 5.37 (s, 1H), 3.78 (s, 2H),3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1.13-0.96 (m, 1H), 0.46 (dd,J=7.6, 2.3 Hz, 2H), 0.13 (dd, J=4.5, 2.3 Hz, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −60.71. MS (ES+) 578.3 (M+1), MS (ES−) 612.3 (M+Cl).;Analysis calculated for C₃₁H₃₀F₃N₅O₃:C, 64.46; H, 5.24; N, 12.12; Found:C, 64.03; H, 5.24; N, 11.77.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149a)

To a solution ofN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(123c) (1.0 g, 1.759 mmol) in dichloromethane (30 mL) cooled to −78° C.was added drop-wise under a positive flow nitrogen tribromoborane (1 Msolution in dichloromethane) (5.28 mL, 5.28 mmol) over a period of 10min. The reaction mixture was allowed to warm to room temperature andstirred at room temperature for 1.5 h. The reaction mixture was quenchedwith cyclopropylmethanol (6.44 mL, 88 mmol), evaporated, this cyclerepeated twice then to dryness. To this residue cyclopropylmethanol(6.44 mL, 88 mmol) and hydrogen chloride (8.79 mL, 35.2 mmol) was addedand refluxed for 16 h. Excess solvent was evaporated, to the flask 5 gsilica gel and chloroform (30 mL) was added and evaporated to dryness.The residue was then purified by flash column chromatography [silica gel40 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149a)(0.485 g, 52% yield) as a white solid which was used as such inthe next step; MS (ES−) 531.1 (M−1), 567.1 (M+Cl);

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149b)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149a) (0.430 g, 0.807 mmol) in anhydrous methanol (10 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.096 g, 0.404 mmol),sodium borohydride (0.244 g, 6.46 mmol) was then added in small portionsover a period of 5 min. The reaction was exothermic and effervescent.The reaction mixture was stirred for 15 min at 0° C., at this pointN1-(2-aminoethyl)ethane-1,2-diamine (0.872 mL, 8.07 mmol) was added. Themixture was allowed to stir for 30 minutes and concentrated in vacuum todryness. The residue was treated with water (50 mL), and extracted withchloroform (2×50 mL), then ethyl acetate (2×50 mL), combined organiclayers were dried over anhydrous MgSO₄, and filtered, excess solventswere pumped-off under reduced pressure. The residue was purified byflash column chromatography [(silica gel 40 g, eluting withCMA80/chloroform from 0 to 100%)] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(149b) (51 mg, 12% yield) as a colorless solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.70 (s, 1H, D₂O exchangeable), 9.37 (s, 1H, D₂Oexchangeable), 7.59-7.51 (m, 4H), 7.45-7.41 (m, 2H), 7.35-7.23 (m, 2H),7.15-7.05 (m, 3H), 6.71 (s, 1H), 6.68 (s, 1H), 5.31 (s, 1H), 3.79 (s,2H), 3.19 (d, J=6.7 Hz, 2H), 2.39 (s, 2H, D₂O exchangeable), 1.11-0.96(m, 1H), 0.44 (ddd, J=7.9, 3.7, 2.5 Hz, 2H), 0.13 (ddd, J=6.7, 3.3, 2.0Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 7.62-7.49 (m, 4H), 7.45 (dd,J=4.8, 2.3 Hz, 2H), 7.36-7.25 (m, 2H), 7.15-7.08 (m, 3H), 6.75-6.68 (m,2H), 5.32 (s, 1H), 3.77 (s, 2H), 3.19 (d, J=6.8 Hz, 2H), 1.11-0.96 (m,1H), 0.45 (ddd, J=7.8, 3.7, 2.4 Hz, 2H), 0.13 (ddd, J=6.7, 3.3, 2.0 Hz,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71; MS (ES⁺): MS (ES+) 537.3(M+1), MS (ES−) 535.3 (M−1), 571.3 (M+Cl); Analysis calculated for:C₂₉H₂₇F₃N₄O₃.0.5H₂O: C, 63.85; H, 5.17; N, 10.27; Found: C, 63.91; H,5.30; N, 10.24.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (150f) Step-1: Preparation of(3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b)

To a stirred solution of 2,3-bis(benzyloxy)benzaldehyde (150a) (3.2 g,10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish(3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b) (2.5 g, 60.75%)as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.53-7.46 (m, 2H),7.41-7.30 (m, 8H), 7.05 (s, 3H), 6.89 (t, J=7.7 Hz, 1H), 6.54 (t, J=1.9Hz, 1H), 6.45 (dt, J=7.7, 1.3 Hz, 1H), 6.37 (ddd, J=8.0, 2.3, 1.1 Hz,1H), 5.90 (d, J=4.4 Hz, 1H), 5.55 (d, J=4.5 Hz, 1H), 5.15 (s, 2H), 4.96(s, 2H), 4.91 (d, J=10.5 Hz, 1H), 4.75 (d, J=10.5 Hz, 1H).

Step-2:N-(3-((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.2 g, 4.26 mmol) in toluene (30 mL) and DMF (15 drops) was added at 0°C. SOCl₂ (1.16 g, 9.79 mmol) and heated at reflux for 3.5 h. Thereaction mixture was cooled to room temperature and concentrated invacuum to dryness. The residue was dissolved in dichloromethane (100 mL)and added (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b) (2.5g, 3.58 mmol), and triethylamine (5 mL). The reaction mixture wasstirred at room temperature for 18 h under nitrogen atmosphere. Thereaction was diluted with ethyl acetate (350 mL) washed with water(2×150 mL), brine (120 mL), dried, filtered, and evaporated to dryness.The residue obtained was purified by flash column chromatography [silicagel 120 g, eluting with ethyl acetate in hexanes from 0-30%] to furnishN-(3-((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150c) (2.4 g, 83.50%) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.8, 1.3 Hz, 1H),7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.76-7.67 (m, 2H), 7.61 (t, J=1.8Hz, 1H), 7.58-7.44 (m, 3H), 7.39 (s, 2H), 7.37-7.24 (m, 6H), 7.22 (t,J=7.9 Hz, 1H), 7.11-6.97 (m, 4H), 6.01 (d, J=4.2 Hz, 1H), 5.81 (d, J=4.3Hz, 1H), 5.15 (s, 2H), 4.99-4.77 (m, 2H).

Step-3:N-(3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150d)

To a solution ofN-(3-((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(3.0 g, 4.44 mmol) in dichloromethane (50 mL) at 0° C. was added thionylchloride (1.0 g, 8.40 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated in vacuum to dryness. The residueobtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (1.26 g, 17.76 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to affordN-(3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150d) (2.0 g, 61.8%) as brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.97 (dt, J=7.8, 1.3 Hz, 1H),7.89 (ddd, J=8.3, 2.3, 1.2 Hz, 1H), 7.75-7.67 (m, 2H), 7.64 (t, J=1.9Hz, 1H), 7.55-7.47 (m, 3H), 7.42-7.27 (m, 8H), 7.22 (t, J=7.9 Hz, 1H),7.07 (d, J=14.4 Hz, 4H), 5.14 (d, J=2.3 Hz, 3H), 4.90 (d, J=2.7 Hz, 2H),2.24 (dt, J=11.4, 5.6 Hz, 1H), 2.18-2.07 (m, 2H), 0.84 (dq, J=9.7, 6.1Hz, 1H), 0.37-0.25 (m, 2H), 0.09-−0.11 (m, 2H).

Step-4: Preparation of tert-butyl3-(5-((3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(150e)

To a solution ofN-(3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150d) (2.0, 2.748 mmol) in MeOH (12 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (0.78 g, 3.297 mmol) and Boc anhydride(1.8 g, 8.244 mmol) followed by portionwise addition of sodiumborohydride (0.623 g, 16.488 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.75 mL, 6.870 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish tert-butyl3-(5-((3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(150e) (0.530 g, 23.18%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.67 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.50 (dt, J=7.8, 2.3 Hz, 4H),7.43-7.39 (m, 3H), 7.37-7.28 (m, 8H), 7.20 (t, J=7.8 Hz, 1H), 7.08 (s,1H), 7.05 (s, 3H), 5.18-5.08 (m, 2H), 4.89 (d, J=2.7 Hz, 2H), 4.18 (d,J=6.2 Hz, 2H), 2.29-2.18 (m, 1H), 2.11 (s, 2H), 1.36 (s, 9H), 1.30-1.20(m, 2H), 0.90-0.78 (m, 2H), 0.36-0.28 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.79; MS (ES+) 832.5 (M+1); (ES−) 830.4 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide(150f)

To a solution of tert-butyl3-(5-(3-((2,3-bis(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(150e) (0.375 g, 0.451 mmol) in dichloromethane (10 mL) cooled to 0° C.was added dropwise under a nitrogen atmosphere borontrichloride (1 Msolution in dichloromethane, 1.8 mL, 1.8 mmol). The reaction mixture wasallowed to warm to room temperature and stirred at room temperature 2 h.The reaction mixture was quenched with methanol (5 mL) and concentratedin vacuum to dryness. The residue obtained was triturated with methanoland dried under vacuum, this step was repeated four times to furnishcrude product. The residue obtained was purified twice by flash columnchromatography [silica gel 12 g and 4 g, eluting with CMA-80 inchloroform from 0-100%] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(150f) (0.02 g, 0.036 mmol, 8.04% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.65 (t, J=1.8 Hz, 1H), 7.59-7.50 (m,3H), 7.46-7.38 (m, 2H), 7.36-7.24 (m, 2H), 7.24-7.16 (m, 1H), 6.59 (dd,J=7.6, 1.9 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.43 (dd, J=7.7, 1.9 Hz,1H), 4.96 (s, 1H), 3.78 (s, 2H), 2.42 (m, 1H), 2.27 (m, 1H), 1.02-0.88(m, 1H), 0.53-0.29 (m, 2H), 0.22-0.02 (m, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−60.70; ¹³C NMR (75 MHz, DMSO) δ 191.41, 173.39, 156.44, 145.17, 145.04,144.57, 143.73, 139.01, 137.92, 128.75, 127.74, 127.15, 123.40, 123.38,123.27, 122.64, 118.82, 118.72, 118.43, 114.03, 64.03, 51.75, 44.67,10.46, 3.49, 3.28; MS (ES+) 552.3 (M+1); (ES−) 550.3 (M−1); Analysiscalculated for C₂₉H₂₈F₃N₅O₃.0.75H₂O: C, 61.64; H, 5.26; N, 12.39; Found:C, 62.01; H, 5.23; N, 11.92.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxy-3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151g) Step-1: Preparation of(3-aminophenyl)(2-(benzyloxy)-3-methoxyphenyl)methanol (151b)

To a stirred solution of 2-(benzyloxy)-3-methoxybenzaldehyde (151a) (3.2g, 10 mmol) in tetrahydrofuran (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish(3-aminophenyl)(2-(benzyloxy)-3-methoxyphenyl)methanol (151b) (3.2 g,86.97%) as a light brown sticky liquid; ¹H NMR (300 MHz, DMSO-d₆) δ7.49-7.30 (m, 5H), 7.10-6.99 (m, 2H), 6.94 (dd, J=7.5, 2.2 Hz, 1H), 6.88(t, J=7.7 Hz, 1H), 6.53 (t, J=1.9 Hz, 1H), 6.44 (dt, J=7.7, 1.3 Hz, 1H),6.37 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 5.52 (d,J=4.4 Hz, 1H), 4.95 (s, 2H), 4.89 (d, J=10.8 Hz, 1H), 4.77 (d, J=10.8Hz, 1H), 3.82 (s, 3H); MS (ES−) 334.3 (M−1).

Step-2: Preparation ofN-(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(3.018, 10.73 mmol) in in DMF (72 mL) was added(3-Amino-phenyl)-(2-benzyloxy-3-methoxy-phenyl)-methanol (151b) (3.2 g,9.54 mmol), N-ethyl-N-isopropylpropan-2-amine (11.097 g, 85.864 mmol)and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 5.003g, 10.73 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 42 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (350 mL) washed with water (2×150 mL), brine(120 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with ethyl acetate in hexanes from 0-30%] to furnishN-(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151c) (2.4 g, 37.36%) as a yellow sticky liquid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.63 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.7, 1.4Hz, 1H), 7.94 (s, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.72 (d,J=8.0 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.54-7.48(m, 1H), 7.43 (dd, J=5.2, 1.6 Hz, 3H), 7.38-7.34 (m, 2H), 7.22 (t, J=7.9Hz, 1H), 7.06-6.99 (m, 3H), 6.00 (d, J=4.4 Hz, 1H), 5.81 (d, J=4.3 Hz,1H), 4.93 (s, 2H), 4.85 (d, J=8.6 Hz, 1H), 4.76 (d, J=10.8 Hz, 1H), 3.82(s, 3H).

Step-3: Preparation ofN-(3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151d)

To a solution ofN-(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151c) (2.0 g, 3.34 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.795 g, 6.68 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (40 mL) and addedcyclopropylmethanamine (3.56 g, 50.1 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (50mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-40% ethyl acetate in hexane) to affordN-(3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151d) (1.01 g, 46.40%) as brown liquid.

Step-4: Preparation of tert-butyl((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (151e) tert-butyl3-(5-((3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(151f)

To a solution ofN-(3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151d) (1.0 g, 1.53 mmol) in MeOH (12 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.40 g, 1.683 mmol) and Bocanhydride (1.00 g, 4.59 mmol) followed by portionwise addition of sodiumborohydride (0.34 g, 9.18 mmol) over a period of 15 min. The reactionmixture was stirred at room temperature for 2 hrs and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.4 mL, 3.825 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness and the residue obtained was dissolved in chloroform(25 mL) and water (25 mL). The aqueous layer was separated extractedwith chloroform (25 mL). The combined extracts were washed with brine(25 mL), dried over MgSO₄ filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with 0-25% Ethyl acetate/hexane) to furnish:

-   -   1. tert-butyl        ((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)        methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)        (cyclopropylmethyl)carbamate (151e) (0.130 g, 9.9%) as an        off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 7.61        (d, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.49 (t, J=6.2 Hz, 1H),        7.44-7.27 (m, 9H), 7.26 (d, J=8.0 Hz, 1H), 7.13-6.99 (m, 2H),        6.77 (d, J=7.7 Hz, 1H), 6.52 (dd, J=6.5, 2.7 Hz, 1H), 4.96 (d,        J=10.8 Hz, 1H), 4.83 (d, J=10.8 Hz, 1H), 4.17 (d, J=6.2 Hz, 2H),        3.86 (s, 3H), 3.82-3.76 (m, 1H), 3.25-3.17 (m, 1H), 2.94 (dd,        J=14.5, 6.9 Hz, 1H), 1.36 (d, J=1.6 Hz, 18H), 0.62-0.46 (m, 1H),        0.27-0.06 (m, 2H), −0.09-−0.23 (m, 1H), −0.32-−0.55 (m, 1H); ¹⁹F        NMR (282 MHz, DMSO) δ −60.79; MS (ES+) 878.5 (M+Na); (ES−) 854.5        (M−1).    -   2. tert-butyl        3-(5-((3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)        methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (151f) (0.020 g, 1.72% as a white solid; 1H NMR (300 MHz,        DMSO-d₆) δ 10.66 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.50 (d,        J=7.3 Hz, 1H), 7.44-7.39 (m, 5H), 7.39-7.28 (m, 5H), 7.19 (t,        J=7.8 Hz, 1H), 7.05 (d, J=4.5 Hz, 1H), 7.02 (s, 1H), 6.93 (dd,        J=7.0, 2.6 Hz, 1H), 5.11 (s, 1H), 4.88 (s, 2H), 4.18 (d, J=6.2        Hz, 3H), 3.82 (s, 3H), 2.16-2.04 (m, 3H), 1.36 (s, 9H),        0.91-0.71 (m, 1H), 0.34-0.28 (m, 2H), −0.03 (dd, J=9.1, 2.7 Hz,        2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.78; MS (ES+) 756.5 (M+1);        (ES−) 754.5 (M−1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxy-3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151g)

To a solution of tert-butyl((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate(151e) (0.012 g, 0.014 mmol) in methanol (10 mL) was added Palladium oncarbon (10%, 0.037 mg) and conc. HCl (0.023 mL, 0.280 mmol). The mixturewas hydrogenated for 2 h at 50 psi and filtered through a pad of celite.The filtrate was concentrated in vacuum to dryness. The residue obtainedwas purified twice by flash column chromatography (silica gel 12 g,eluting 0-100% CMA-80 in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxy-3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(151g) (0.013 g, 0.023 mmol, 16.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.73 (s, 1H), 7.66-7.61 (m, 1H), 7.60-7.49 (m, 3H),7.48-7.38 (m, 2H), 7.35-7.23 (m, 2H), 7.19 (dt, J=7.9, 1.4 Hz, 1H), 6.77(dd, J=6.5, 3.1 Hz, 1H), 6.64 (d, J=6.6 Hz, 2H), 5.01 (s, 1H), 3.77 (s,2H), 3.72 (s, 3H), 2.44-2.20 (m, 2H), 1.03-0.87 (m, 1H), 0.49-0.30 (m,2H), 0.17-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.70; MS (ES+) 566.3(M+1); (ES−) 564.3 (M−1); Analysis calculated for C₃₀H₃₀F₃N₅O₃.2H₂O: C,59.89; H, 5.70; N, 11.64; Found: C, 59.69; H, 5.27; N, 11.36.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (152d)Step-1: Preparation of 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile(152a)

To a stirred solution of 3-formylbenzonitrile (54a) (3.93 g, 30 mmol) intetrahydrofuran (50 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (36.0 mL,36.0 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature and quenched by adding 2 N HCl (37.5 mL, 75 mmol), stirredfor additional 1 h at room temperature. The reaction mixture was treatedwith 2 N NaOH (45 mL, 90 mmol) and extracted with ethyl acetate (2×100mL). The organic layers were combined washed with sat. NH₄Cl (100 mL),dried over anhydrous MgSO₄, filtered, evaporated to dryness. The cruderesidue was purified by flash column chromatography (silica gel 120 g,eluting with 0-100% ethyl acetate in hexane) to furnish3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (152a) (3.56 g, 15.87mmol, 52.9% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.76(t, J=1.6 Hz, 1H), 7.72-7.63 (m, 2H), 7.51 (t, J=7.7 Hz, 1H), 6.94 (t,J=7.7 Hz, 1H), 6.61-6.48 (m, 2H), 6.41 (ddd, J=8.0, 2.4, 1.1 Hz, 1H),5.96 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.59 (d, J=3.9 Hz, 1H), 5.04(s, 2H, D₂O exchangeable); MS (ES+) 225.2 (M+1), 247.1 (M+Na); MS (ES−)223.1 (M−1), 447.2 (2M−1).

Step-2: Preparation of tert-butyl3-(5-(3-((3-cyanophenyl)(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152b)

A single-necked 100 mL flask was charged with1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (7.27 g, 18.86 mmol),3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (152a) (3.524 g, 15.71mmol), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP,8.79 g, 18.86 mmol) were treated N,N-dimethylformamide (91 mL) andN-ethyl-N-isopropylpropan-2-amine (13.69 mL, 79 mmol) successively in apositive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. The residue was treated with water (75 mL), andextracted with ethyl acetate (2×75 mL) combined organics were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue was thenpurified by flash column chromatography [silica gel 80 g, eluting withethyl acetate in hexanes from 0-100%] to furnish tert-butyl3-(5-(3-((3-cyanophenyl)(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152b) (3.799 g, 6.42 mmol, 40.9% yield) as a yellow solid; ¹H NMR: 1HNMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H, D₂O exchangeable), 7.80 (t, J=1.7Hz, 1H), 7.69 (ddt, J=8.6, 5.7, 1.5 Hz, 2H), 7.62 (t, J=1.7 Hz, 1H),7.60-7.55 (m, 2H), 7.54-7.39 (m, 3H), 7.38-7.25 (m, 3H), 7.16 (dt,J=7.7, 1.3 Hz, 1H), 6.20 (d, J=3.9 Hz, 1H, D₂O exchangeable), 5.76 (d,J=3.9 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H); 19F NMR (282 MHz,DMSO-d₆) δ −60.78; IR (KBr, cm⁻¹): 2232 cm⁻¹ (—CN stretching); MS (ES⁺):MS (ES+) 614.3 (M+Na), MS (ES−) 590.3 (M−1), 626.3 (M+Cl).

Step-3: Preparation of tert-butyl3-(5-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152c)

To a solution of tert-butyl3-(5-(3-((3-cyanophenyl)(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152b) (3.71 g, 6.27 mmol) in dichloromethane (40 mL) at 0° C. was addedthionyl chloride (1.372 mL, 18.81 mmol), reaction mixture allowed towarm to room temperature and stirred for 3 h. The reaction mixture wasquenched with cyclopropylmethanamine (3.81 mL, 43.9 mmol), and solutionwas stirred for 30 min at room temperature, and concentrated in vacuumto dryness. The residue was dissolved in acetonitrile (40 mL) then addedcyclopropylmethanamine (3.81 mL, 43.9 mmol) stirred at 80° C. for 16 h,TLC analysis (ethyl acetate/hexanes, 1:1, v/v) shows completeconversion, reaction mixture was cooled to room temperature. Thereaction mixture treated silica gel (6 g), evaporated under reducedpressure until become dry slurry. The residue was purified by flashcolumn chromatography (silica gel 40 g, performed two separate columns,eluting with ethyl acetate in hexanes from 0-100%) to afford tert-butyl3-(5-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152c) (0.704 g, 17% yield) as a white solid which was used as such inthe next step; MS (ES+) 645.1 (M+1); MS (ES−) 643.2 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(152d)

To a solution of tert-butyl3-(5-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(152c) (0.285 g, 0.442 mmol) in dioxane (9 mL) was added hydrogenchloride (4 N) (3.17 mL, 19.01 mmol), reaction mixture stirred at roomtemperature and stirred for 16 h. The reaction mixture was concentratedin vacuum and residue obtained was purified by flash columnchromatography (silica gel 25 g, eluting with methanol in chloroformfrom 0-100%) to afford1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(152d) (39 mg, 16% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.76 (s, 1H, D₂O exchangeable), 7.87 (t, J=1.7 Hz, 1H), 7.74 (dt,J=7.8, 1.5 Hz, 1H), 7.67 (ddd, J=7.9, 3.6, 2.2 Hz, 4H), 7.61-7.43 (m,5H), 7.32-7.18 (m, 2H), 4.91 (s, 1H), 4.04 (s, 2H), 2.26 (dt, J=9.4, 4.8Hz, 2H), 1.02-0.83 (m, 1H), 0.44-0.33 (m, 2H), 0.05 (tt, J=5.8, 3.2 Hz,2H); ¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 7.86 (t, J=1.7 Hz, 1H), 7.78-7.73(m, 1H), 7.70-7.62 (m, 3H), 7.60-7.49 (m, 5H), 7.46 (dt, J=6.3, 2.5 Hz,1H), 7.34-7.19 (m, 2H), 4.92 (s, 1H), 4.02 (s, 2H), 2.34-2.21 (m, 2H),0.98-0.84 (m, 1H), 0.44-0.35 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.76; IR (KBr, cm⁻¹): 2230 cm⁻¹ (—CN stretching); MS(ES⁺): MS (ES+) 545.3 (M+1), MS (ES−) 543.3 (M−1); Analysis calculatedfor: C₃₀H₂₇F₃N₆O.2H₂O.2HCl: C, 55.14; H, 5.09; N, 12.86; Found: C,55.41; H, 5.30; N, 12.20.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethyl-amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(153b) Step-1: Preparation of tert-butyl3-(5-(5-((4-carbamoylphenyl)(cyclopropylmethyl-amino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(153a)

To a solution of tert-butyl3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(52g) (161 mg, 0.243 mmol) in ethanol (6 mL) was added conc. aqueousammonia (2.4 mL) followed by dropwise addition of hydrogen peroxide (30%aq. solution, 0.09 mL). The reaction mixture was stirred at roomtemperature for 21 h and concentrated in vacuum to dryness. The residuewas purified by flash column chromatography [silica gel 4 g, elutingwith chloroform/methanol (1:0 to 19:1)] to give tert-butyl3-(5-(5-((4-carbamoylphenyl)(cyclopropylmethyl-amino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(153a) (17 mg, 10%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H), 7.88 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.66-7.26 (m, 9H),7.20 (t, J=9.6 Hz, 1H), 4.90 (s, 1H), 4.19 (d, J=6.1 Hz, 2H), 2.30-2.22(m, 2H), 1.37 (s, 9H), 0.99-0.80 (m, 1H), 0.46-0.31 (m, 2H), 0.10-−0.03(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −123.53; MS (ES+): 681.4(M+H).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(153b)

To a solution of tert-butyl3-(5-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(153a) (15 mg, 0.022 mmol) in 1,4-Dioxane (4 mL) was added hydrogenchloride (0.240 mL, 0.961 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 16 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel elutingwith chloroform/CMA80 (1:0 to 2:1)] to give1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(153b). The purified product was dissolved in methanol (10 mL) andtreated with 4 N HCl (aq. 0.03 mL) followed by concentration to drynessto give1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(153b) (19 mg) hydrochloride salt as a off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.81 (s, 1H), 10.26 (s, 2H), 8.43 (s, 3H), 8.04 (s, 1H),7.95 (s, 1H), 7.94-7.87 (m, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.74-7.68 (m,3H), 7.64-7.51 (m, 2H), 7.47 (s, 1H), 7.41 (dd, J=10.3, 8.6 Hz, 1H),5.73 (t, J=6.3 Hz, 1H), 4.12 (q, J=5.9 Hz, 2H), 2.72 (d, J=8.9 Hz, 2H),1.23-1.08 (m, 2H), 0.64-0.46 (m, 2H), 0.41-0.20 (m, 1H); ¹H NMR (D₂O exNMR, 300 MHz, DMSO-d₆) δ 7.95-7.82 (m, 3H), 7.73-7.48 (m, 8H), 7.43 (dd,J=10.2, 8.6 Hz, 1H), 5.70 (s, 1H), 4.12 (s, 2H), 2.78-2.72 (m, 2H),1.21-0.97 (m, 1H), 0.66-0.54 (m, 2H), 0.33-0.24 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.81, −120.35; MS (ES+): 581.3 (M+1); Analysiscalculated for C₃₀H₂₈F₄N₆O₂.2HCl.3H₂O: C, 50.93; H, 5.13; N, 11.88;Found: C, 50.56; H, 5.23; N, 11.55.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154e) Step-1: Preparation of(3-aminophenyl)(4-methoxynaphthalen-1-yl)methanol (154b)

To a stirred solution of 4-methoxy-1-naphthaldehyde (154a) (2.048 g, 11mmol) in tetrahydrofuran (30 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (13.20 mL,13.20 mmol) at 0° C. The reaction was stirred for 15 h at temperatureand quenched by slowly adding aq. 12 N HCl (2.292 mL, 27.5 mmol), andstirred for 1 h. The reaction mixture was treated with 1 N NaOH (16.50mL, 33.0 mmol) and extracted with ethyl acetate (2×50 mL). The organiclayers were combined, dried over anhydrous MgSO₄, filtered, andevaporated to dryness. The residue was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% ethyl acetate inhexane) to furnish (3-aminophenyl)(4-methoxynaphthalen-1-yl)methanol(154b) (2.818 g, 92% yield) as a off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.25-8.00 (m, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.43 (dt, J=6.5,3.4 Hz, 2H), 7.01-6.85 (m, 2H), 6.54 (dp, J=3.4, 1.4 Hz, 2H), 6.37 (ddd,J=7.9, 2.2, 1.0 Hz, 1H), 6.08 (d, J=4.4 Hz, 1H), 5.74 (d, J=4.4 Hz, 1H,D₂O exchangeable), 4.95 (s, 2H, D₂O exchangeable), 3.96 (s, 3H); MS(ES⁺): MS (ES+) 302.2 (M+Na), MS (ES−) 278.3 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154c)

In a 250 mL single-necked flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(3.30 g, 11.73 mmol), (3-aminophenyl)(4-methoxynaphthalen-1-yl)methanol(154b) (2.73 g, 9.77 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 5.47 g, 11.73 mmol) was addedN,N-dimethylformamide (56.8 mL, 733 mmol) andN-ethyl-N-isopropylpropan-2-amine (DIPEA, 8.51 mL, 48.9 mmol)successively in a positive flow of nitrogen at room temperature. Theresulting reaction mixture was stirred for 16 h at room temperatureunder a positive flow of nitrogen. The reaction mixture was treated withwater (150 mL), and extracted with chloroform (2×100 mL), combinedorganics were dried over anhydrous MgSO₄, filtered, evaporated todryness. The residue was purified by flash column chromatography [silicagel 40 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154c) (4.274 g, 81% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.60 (s, 1H, D₂O exchangeable), 8.21-8.13 (m, 2H), 8.06 (dt,J=7.7, 2.7 Hz, 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.88 (ddd, J=8.2, 2.2,1.1 Hz, 1H), 7.77-7.66 (m, 2H), 7.58 (dd, J=6.7, 1.4 Hz, 2H), 7.52 (d,J=8.0 Hz, 1H), 7.48-7.38 (m, 2H), 7.26 (t, J=8.2 Hz, 1H), 7.20-7.13 (m,1H), 6.97 (d, J=8.0 Hz, 1H), 6.23 (d, J=4.3 Hz, 1H), 6.02 (d, J=4.3 Hz,1H, D₂O exchangeable), 3.97 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.96; MS (ES⁺): MS (ES+) 565.3 (M+Na), MS (ES−) 541.2 (M−1); IR (KBr,cm⁻¹): 2235 cm⁻¹ (—CN stretching).

Step-3: Preparation of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154d)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154c) (2.693 g, 4.96 mmol) in dichloromethane (40 mL) at 0° C. wasadded thionyl chloride (1.086 mL, 14.89 mmol) and allowed to warm toroom temperature and stirred for 3 h. The reaction mixture was quenchedwith cyclopropylmethanamine (2.98 mL, 34.7 mmol) and stirred for 1 h atroom temperature, and then concentrated in vacuum to dryness. Theresidue was dissolved in cyclopropylmethanamine (8.51 mL, 99 mmol) andacetonitrile (40 mL) and the reaction mixture was heated at 80° C. for16 h. TLC analysis (CHCl₃/MeOH, 9/1, v/v) shows reaction was complete,reaction mixture was evaporated to dryness. The residue was purified byflash column chromatography (First column silica gel 40 g, second column80 g, eluting methanol in chloroform from 0-50%) to afford1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154d) (1.64 g, 55% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H, D₂O exchangeable), 8.24-8.12 (m, 3H), 7.99 (dt,J=7.7, 1.3 Hz, 1H), 7.93-7.84 (m, 1H), 7.78-7.41 (m, 8H), 7.26 (q,J=3.7, 2.5 Hz, 2H), 6.98 (d, J=8.2 Hz, 1H), 5.52 (s, 1H), 3.95 (s, 3H),2.39 (d, J=6.6 Hz, 2H), 1.08-0.89 (m, 1H), 0.38 (dd, J=7.6, 6.0 Hz, 2H),0.06 (td, J=4.5, 3.8, 2.5 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.94;MS (ES⁺): MS (ES+) 596.3 (M+1), MS (ES−) 594.3 (M−1); IR (KBr, cm⁻¹):2234 cm⁻¹ (—CN stretching).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154e)

To a stirred solution of1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154d) (1.51 g, 2.54 mmol) in anhydrous methanol (10 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.301 g, 1.268 mmol),sodium borohydride (0.767 g, 20.28 mmol) was then added in smallportions over 5 min. The reaction was exothermic and effervescent. Thereaction mixture was stirred for 15 min at 0° C., at this pointN1-(2-aminoethyl)ethane-1,2-diamine (2.74 mL, 25.4 mmol) was added. Themixture was allowed to stir for 30 minutes more before solvent wasevaporated. The residue was treated with water (30 mL), and extractedwith chloroform (2×30 mL), then ethyl acetate (2×30 mL), combinedorganic layers were dried over anhydrous MgSO₄, and filtered, excesssolvents were pumped-off under reduced pressure. The residue waspurified by flash column chromatography [(silica gel 40 g, eluting withCMA80/chloroform from 0 to 100%)] to furnish 430 mg1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154e) free-base as a yellow oil which was taken and dissolved inmethanol, to this solution 2 N HCl (1.901 mL, 3.80 mmol) was addeddrop-wise, stirred for 30 min evaporated to dryness to afford1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(154e) (483 mg, 32% yield) hydrochloride as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.23 (s, 1H, D₂O exchangeable), 10.02(s, 1H, D₂O exchangeable), 8.53 (s, 3H, D₂O exchangeable), 8.29-8.10 (m,3H,), 7.86 (t, J=1.8 Hz, 1H), 7.77-7.35 (m, 11H), 7.13 (d, J=8.2 Hz,1H), 6.45-6.19 (m, 1H), 4.11 (q, J=6.2 Hz, 2H), 4.01 (s, 3H), 3.01-2.72(m, 2H), 1.19 (ddt, J=10.6, 7.4, 3.5 Hz, 1H), 0.55 (dd, J=8.0, 3.7 Hz,2H), 0.41-0.16 (m, 2H); ¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 10.93 (s, 1H),8.30-8.22 (m, 1H), 8.19-8.11 (m, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.80 (d,J=2.3 Hz, 1H), 7.71-7.61 (m, 3H), 7.61-7.56 (m, 4H), 7.54 (s, 1H),7.51-7.42 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 6.31 (s, 1H), 4.12 (s, 2H),4.02 (s, 3H), 3.07-2.73 (m, 2H), 1.14 (tt, J=8.6, 4.7 Hz, 1H), 0.71-0.47(m, 2H), 0.42-0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77; MS(ES⁺): MS (ES+) 600.3 (M+1), MS (ES−) 598.3 (M−1); Analysis calculatedfor: C₃₄H₃₂F₃N₅O₂.2.5HCl 1.75H₂O-0.17CHCl₃: C, 55.26; H, 5.18; Cl,14.37; N, 9.43; Found: C, 55.33; H, 5.04; Cl, 14.59; N, 9.28.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155c) Step-1: Preparation of1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155a)

A single-necked 100 mL flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(3.42 g, 12.16 mmol),3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (1.964 g,8.11 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 4.54 g, 9.73 mmol) was addedN,N-dimethylformamide (47 mL) and N-ethyl-N-isopropylpropan-2-amine(7.06 mL, 40.5 mmol) successively in a positive flow of nitrogen at roomtemperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere.Excess DMF was pumped-off under reduced pressure. The residue wastreated with sat. NH₄Cl (30 mL), and extracted with ethyl acetate (2×50mL) combined organics were dried over anhydrous MgSO₄, filtered,evaporated to dryness. The residue was then purified by flash columnchromatography [silica gel 40 g, eluting with methanol in chloroformfrom 0-100%] to furnish1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155a) (1.479 g, 2.93 mmol, 36.1% yield) as a white solid; MS (ES⁺): MS(ES+) 265.2 (M+Na), MS (ES−) 504.2 (M−1).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155b)

To a solution of1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155a) (1.003 g, 1.984 mmol) in dichloromethane (20 mL) at 0° C. wasadded thionyl chloride (0.434 mL, 5.95 mmol), reaction mixture allowedto warm to room temperature and stirred for 3 h. The reaction mixturewas quenched with cyclopropylmethanamine (1.205 mL, 13.89 mmol), andsolution was stirred for 30 min at room temperature, and concentrated invacuum to dryness. The residue was dissolved acetonitrile (20 mL), addedcyclopropylmethanamine (1.205 mL, 13.89 mmol) and stirred at 80° C. for16 h. The reaction mixture was cooled to room temperature, concentratedin vacuum and the residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with methanol in chloroformfrom 0-100%) to afford1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155b) (376 mg, 34% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.54 (s, 1H, D₂O exchangeable), 8.16-8.09 (m, 1H), 8.00 (dt, J=7.7,1.3 Hz, 1H), 7.95-7.86 (m, 2H), 7.79-7.64 (m, 4H), 7.62-7.55 (m, 1H),7.51 (t, J=7.7 Hz, 1H), 7.36 (ddd, J=7.4, 4.8, 2.2 Hz, 1H), 7.23 (dd,J=10.3, 8.5 Hz, 1H), 4.94 (d, J=3.2 Hz, 1H), 2.72 (d, J=4.8 Hz, 1H, D₂Oexchangeable), 2.25 (t, J=6.0 Hz, 2H), 1.01-0.82 (m, 1H), 0.44-0.31 (m,2H), 0.05 (td, J=5.1, 1.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97,−122.76; MS (ES⁺): MS (ES+) 559.3 (M+1), MS (ES−) 557.2 (M−1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155c)

To a stirred solution of1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155b) (351 mg, 0.628 mmol) in anhydrous methanol (10 mL), cooled to 0°C., were added nickel(II) chloride hexahydrate (0.149 g, 0.628 mmol),sodium borohydride (0.380 g, 10.05 mmol) was then added in smallportions over 5 min. The reaction was stirred for 15 min at 0° C.,quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.358 mL, 12.57mmol), stirred for additional 30 mins and concentrated in vacuum. Theresidue was treated with water (30 mL), and extracted with chloroform(2×30 mL), then ethyl acetate (2×30 mL), combined organic layers weredried over anhydrous MgSO₄, and filtered, excess solvents werepumped-off under reduced pressure. The residue was purified by flashcolumn chromatography [(silica gel 40 g, eluting with CMA80/chloroformfrom 0 to 100%)] to furnish1-(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155c) (83 mg) free-base as a waxy solid which was dissolved in methanoland added 2 N HCl (0.566 mL, 1.131 mmol) (7.5 eq), stirred for 30 minevaporated to dryness to afford1-(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(155c) (78 mg, 22% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.90 (s, 1H, D₂O exchangeable), 10.21 (s, 2H, D₂Oexchangeable), 8.46 (s, 7H, D₂O exchangeable), 8.02-7.91 (m, 1H),7.87-7.68 (m, 5H), 7.67-7.46 (m, 5H), 7.40 (dd, J=10.3, 8.6 Hz, 1H),5.73-5.51 (m, 1H), 4.12 (d, J=5.8 Hz, 2H), 4.00 (d, J=5.7 Hz, 2H), 2.71(d, J=7.6 Hz, 2H), 1.16 (s, 1H), 0.67-0.44 (m, 2H), 0.40-0.22 (m, 2H);¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 7.90 (d, J=6.8 Hz, 1H), 7.76-7.48 (m,10H), 7.47-7.37 (m, 1H), 5.63 (s, 1H), 4.12 (s, 2H), 4.03 (s, 2H), 2.74(d, J=7.5 Hz, 2H), 1.10 (s, 1H), 0.58 (d, J=7.6 Hz, 2H), 0.41-0.23 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.59, −119.65. MS (ES⁺): MS (ES+)567.3 (M+1), MS (ES−) 565.3 (M−1), 601.3 (M+Cl); Analysis calculated forC₃₀H₃₀F₄N₆O.4.25H₂O.3.05HCl: C, 47.76; H, 5.55; Cl, 14.33; N, 11.14;Found: C, 47.58; H, 5.16; Cl, 14.65; N, 10.96.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156c) Step-1: Preparation of3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)aniline (156a)

To a stirred solution of1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d) (0.955g, 3.56 mmol) in dichloromethane (40 mL) was added thionyl chloride(1.039 mL, 14.23 mmol) at room temperature. The reaction was stirredovernight at room temperature and quenched with methanol (2.88 mL, 71.2mmol) and triethylamine (4.96 mL, 35.6 mmol). The mixture was stirred atroom temperature for 1 h and concentrated in vacuum. The crude residuewas purified twice by flash column chromatography [silica gel 40 g,eluting with methanol in chloroform (0 to 10% to 100%)] to afford3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)aniline (156a) (491mg, 48.9% yield). MS (ES+): 283.3 (M+H) and(E)-3-(3-cyclopropyl-1-(pyridin-3-yl)prop-1-enyl)aniline (250 mg, 0.999mmol, 28.1% yield). MS (ES+): 251.2 (M+H).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156b)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.526 g, 1.870 mmol) in N,N-Dimethylformamide (10 mL) was added3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)aniline (156a) (0.48g, 1.700 mmol), N-ethyl-N-isopropylpropan-2-amine (1.480 mL, 8.50 mmol)and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 0.792g, 1.700 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 20 h under nitrogen atmosphere. The reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(2×200 mL). The organic layers were combined, washed with water (2×100mL), brine (50 mL), dried, filtered, and evaporated in vacuum todryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with CMA 80 in chloroform) togive1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156b) (332 mg, 36%); MS (ES+), 546.3 (M+1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156c)

To a stirred solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156b) (0.295 g, 0.541 mmol) in methanol (20 mL) at 0° C. was addednickel(II) chloride (0.088 g, 0.676 mmol). To this sodiumtetrahydroborate (0.205 g, 5.41 mmol) was added in small portions over aperiod of 15 minutes. The reaction was stirred for 30 minutes andquenched by adding N1-(2-aminoethyl)ethane-1,2-diamine (0.449 mL, 4.33mmol) and stirred for additional 30 minutes at room temperature. Thereaction mixture was concentrated to remove methanol. The reactionmixture was diluted with water (50 mL) and stirred for 12 hours. Thesolid separated was collected by filtration. The solid was suspended inethanol (100 mL) and concentrated to remove water. The residue waspurified by flash column chromatography (silica gel, 12 g eluting withCMA 80 in chloroform) to afford1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156c) (89 mg, 0.162 mmol, 29.9% yield) free base as a colorless solid.¹HNMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H, D₂O exchangeable), 8.52 (d,J=2.2 Hz, 1H), 8.41 (dd, J=4.7, 1.6 Hz, 1H), 7.72-7.56 (m, 4H), 7.51 (s,1H), 7.42 (d, J=6.6 Hz, 2H), 7.37-7.24 (m, 3H), 7.09 (d, J=8.0 Hz, 1H),3.77 (s, 2H), 3.01 (s, 3H), 2.46-2.40 (m, 2H), 1.99 (s, 2H, D₂Oexchangeable), 0.92 (h, J=8.1 Hz, 2H), 0.66 (t, J=7.0 Hz, 1H), 0.35 (dt,J=8.2, 3.0 Hz, 2H), −0.02-−0.21 (m, 2H); Mass spec (ES+) 550.4; (ES−)548.3 (M−1), 584.3 (M+35); Analysis calculated forC₃₀H₃₀F₃N₅O₂(H₂O)_(0.5): C, 64.48; H, 5.51; N, 12.54; Found: C, 64; 79H, 5.51; N, 12.27.

To a solution of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156c) free base (50 mgs) suspended in hydrogen chloride (3 M solutionin isopropanol, 2 mL, 6.00 mmol) was stirred for 30 mins andconcentrated in vacuum to dryness to afford1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(156c) hydrochloride salt as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.81 (s, 1H), 8.71 (s, 1H), 8.67 (d, J=5.4 Hz, 1H), 8.39 (s, 3H, D₂Oexchangeable), 8.11 (d, J=7.9 Hz, 1H), 7.79-7.47 (m, 9H), 7.32 (t, J=7.9Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 3.04 (s, 3H),2.44 (dt, J=3.9, 2.3 Hz, 2H), 1.00-0.75 (m, 2H), 0.67 (s, 1H), 0.46-0.29(m, 2H), −0.07 (q, J=3.7, 3.1 Hz, 2H); Analysis calculated forC₃₀H₃₀F₃N₅O₂.2.25HCl.2H₂O.0.5C₃H₈₀: C, 54.29; H, 5.82; N, 10.05; Cl,11.30; Found: C, 54.73; H, 5.65; N, 10.00; Cl, 11.48.

Preparation of1-(4-chlorophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(157a)

In a 50 mL single-necked flask containing1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(12c) (0.291 g, 1.001 mmol),1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (0.344 g, 1.202 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (0.560 g, 1.202 mmol) was addedN,N-dimethylformamide (10 mL) and N-ethyl-N-isopropylpropan-2-amine(0.872 mL, 5.01 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere. Thereaction was diluted with ethyl acetate (50 mL) washed with water (50mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). Theorganics layers were combined dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue was purified by flash columnchromatography [silica gel 25 g, eluting with ethyl acetate in hexanesfrom 0-100%] to furnish1-(4-chlorophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(157a) (436 mg, 78% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.50 (s, 1H, D₂O exchangeable), 8.49 (ddd, J=4.9, 1.8, 0.9 Hz, 1H),7.78-7.68 (m, 2H), 7.67-7.53 (m, 6H), 7.41 (ddd, J=8.7, 4.8, 2.3 Hz,1H), 7.24-7.11 (m, 2H), 5.83 (s, 1H, D₂O exchangeable), 2.46-2.27 (m,2H), 1.03 (ddt, J=18.2, 12.4, 7.1 Hz, 2H), 0.57 (d, J=12.5 Hz, 1H),0.42-0.20 (m, 2H), −0.04-−0.18 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.88, −124.19; MS (ES⁺): MS (ES+) 559.2 (M+1), MS (ES−) 557.3 (M−1).

Preparation of1-(6-chloronaphthalen-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(158a)

In a 50 mL single-necked flask containing1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (14d) (0.200 g, 0.587 mmol),1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (0.202 g, 0.704 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (0.328 g, 0.704 mmol) was addedN,N-dimethylformamide (6 mL) and N-ethyl-N-isopropylpropan-2-amine(0.511 mL, 2.94 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere. Thereaction was diluted with ethyl acetate (30 mL) and washed with water(30 mL). The aqueous layer was again extracted with ethyl acetate (2×30mL). The organics layers were combined washed with water (30 mL), driedover anhydrous MgSO₄, filtered and evaporated to dryness. The residuewas purified by flash column chromatography [silica gel 25 g, elutingwith ethyl acetate in hexanes from 0-100%] to furnish1-(6-chloronaphthalen-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(158a) (0.235 g, 0.386 mmol, 65.7% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.56 (s, 1H, D₂O exchangeable), 8.48 (d, J=4.7 Hz, 1H),8.18 (s, 2H), 8.06 (t, J=10.0 Hz, 2H), 7.67 (dq, J=17.8, 8.7 Hz, 6H),7.39 (s, 1H), 7.26-7.08 (m, 2H), 5.81 (s, 1H, D₂O exchangeable),2.44-2.27 (m, 2H), 1.00 (s, 2H), 0.57 (s, 1H), 0.30 (d, J=7.7 Hz, 2H),−0.13 (d, J=4.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.67, −123.96;¹H NMR (300 MHz, DMSO-d₆) D₂O δ 8.48 (dt, J=4.7, 1.4 Hz, 1H), 8.18 (t,J=2.0 Hz, 2H), 8.07 (t, J=8.9 Hz, 2H), 7.80-7.56 (m, 6H), 7.40 (ddd,J=8.8, 4.8, 2.4 Hz, 1H), 7.27-7.10 (m, 2H), 2.45-2.28 (m, 2H), 0.98(ddt, J=19.9, 14.0, 7.2 Hz, 2H), 0.57 (q, J=6.8, 6.2 Hz, 1H), 0.38-0.24(m, 2H), −0.13 (h, J=3.6 Hz, 2H); MS (ES⁺): MS (ES+) 609.3 (M+), 632.2(M+Na), MS (ES−) 608.1 (M−1).

Preparation of1-(5-chloropyridin-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(159a)

In a 50 mL single-necked flask containing1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (13d) (7 mg, 0.024 mmol),1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (10.31 mg, 0.036 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 0.013 g, 0.029 mmol) was addedN,N-dimethylformamide (0.232 mL) and N-ethyl-N-isopropylpropan-2-amine(0.021 mL, 0.120 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere. Thereaction was diluted with ethyl acetate (25 mL) and washed with water(25 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL).The combined organics layers were washed with water (25 mL), brine (25mL) dried over anhydrous MgSO₄, filtered, evaporated to dryness. Theresidue was purified by flash column chromatography [silica gel 4g,eluting with ethyl acetate in hexanes from 0-100%] to furnish1-(5-chloropyridin-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(159a) (5 mg, 37% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.29 (s, 1H, D₂O exchangeable), 8.70 (d, J=2.5 Hz, 1H), 8.51(dt, J=4.9, 1.4 Hz, 1H), 8.34 (dd, J=8.8, 2.6 Hz, 1H), 8.15 (d, J=8.8Hz, 1H), 7.81-7.72 (m, 2H), 7.70-7.64 (m, 2H), 7.44 (ddd, J=8.7, 4.7,2.3 Hz, 1H), 7.28-7.15 (m, 2H), 5.86 (s, 1H, D₂O exchangeable),2.45-2.34 (m, 2H), 1.11-1.01 (m, 2H), 0.61 (td, J=7.5, 3.9 Hz, 1H),0.37-0.31 (m, 2H), −0.08 (dt, J=4.7, 2.0 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −56.83, −124.52; MS (ES⁺): MS (ES+) 560.2 (M+1); MS (ES−)558.2 (M−1).

Preparation ofN-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(160a)

A single-necked 50 mL flask containing1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(11c) (100 mg, 0.349 mmol),1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol(59a) (0.120 g, 0.419 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 0.195 g, 0.419 mmol) were treatedN,N-dimethylformamide (3.38 mL, 43.7 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.304 mL, 1.747 mmol) successively ina positive flow of nitrogen at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h under a positive flowof nitrogen atmosphere. The reaction was diluted with ethyl acetate (30mL) and washed with water (30 mL). The aqueous layer was again extractedwith ethyl acetate (2×30 mL). The combined organics layers were washedwith water (30 mL), brine (30 mL), dried over anhydrous MgSO₄, filteredand evaporated to dryness. The residue was purified by flash columnchromatography [first column: silica gel 12 g, eluting with ethylacetate in hexanes from 0-100%, second column: silica gel 12 g, elutingwith ethyl acetate in hexanes from 0-20%] to furnishN-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(160a) (31 mg, 16% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.43 (s, 1H, D₂O exchangeable), 8.49 (ddd, J=4.8, 1.8, 0.9 Hz, 1H),7.73 (td, J=7.7, 1.9 Hz, 2H), 7.63 (dt, J=8.0, 1.1 Hz, 1H), 7.55 (s,1H), 7.48-7.35 (m, 3H), 7.25-7.11 (m, 2H), 7.07-6.99 (m, 2H), 5.82 (s,1H, D₂O exchangeable), 3.81 (s, 3H), 2.45-2.25 (m, 2H), 1.01 (dddd,J=25.1, 13.6, 9.9, 6.3 Hz, 2H), 0.71-0.50 (m, 1H), 0.39-0.25 (m, 2H),−0.10 (h, J=3.4 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71, −124.38;MS (ES⁺): MS (ES+) 555.3 (M+1), 577.3 (M+Na), 553.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(161e) Step-1: Preparation of tert-butyl6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161b)

To a solution of tert-butyl7-fluoro-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161a) (0.5g, 1.688 mmol) (Prepared as described in the literature (a) Harling, J.D; Watson, N. S.; Young, R. J. WO 2006/108709 A1 Oct. 19, 2006; (b)Watson, N. S.; Adams, C.; Belton, D.; Brown, D.; Burns-Kurtis, C. L.;Chaudry, L.; Chan, C.; Convery, Maire A.; Davies, D. E.; Exall, A. M. etal, Bioorganic & Medicinal Chemistry Letters (2011), 21(6), 1588-1592)in methanol (20 mL) was added palladium on carbon (10%) (0.359 g, 3.38mmol) and hydrogenated for 3 h at 60 psi. The catalyst was removed byfiltration through Celite and the filtrate was concentrated in vacuum.The residue was purified by flash column chromatography [silica gel 12g, eluting with ethyl acetate in hexanes from 0-100%] to furnishtert-butyl 6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161b) (0.256 g, 57% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 6.81 (d, J=12.0 Hz, 1H), 6.51 (d, J=9.1 Hz, 1H), 4.98 (s, 2H, D₂Oexchangeable), 4.31 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.59 (t, J=5.9 Hz,2H), 1.41 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.71; MS (ES⁺): MS(ES+) 289.2 (M+Na), 555.4 (2M+Na), MS (ES−) 265.1 (M−1); Analysiscalculated for C₁₄H₁₉FN₂O₂: C, 63.14; H, 7.19; N, 10.52; Found: C,63.41; H, 7.27; N, 10.43.

Step-2: Preparation of tert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161c)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.250 g, 0.889 mmol) in N,N-dimethylformamide (6 mL) was addedtert-butyl 6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161b) (0.237 g, 0.889 mmol), N-ethyl-N-isopropylpropan-2-amine (1.239mL, 7.11 mmol) and Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBroP) (0.456 g, 0.978 mmol) at room temperature. The resultingreaction mixture was stirred at 20° C. for 16 h. The reaction mixturewas quenched with water (25 mL) and extracted with ethyl acetate (50 mL,20 mL, 20 mL). The organic layers were combined washed with water (25mL), brine (25 mL), dried over MgSO₄, filtered, concentrated in vacuumto dryness. The residue purified by flash column chromatography (silicagel 25 g, eluting with hexanes in ethyl acetate from 0-100%) to furnishtert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161c) (235 mg, 50% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.51 (s, 1H, D₂O exchangeable), 8.12 (t, J=1.9 Hz, 1H), 8.00 (dt,J=7.7, 1.3 Hz, 1H), 7.95-7.85 (m, 1H), 7.80-7.68 (m, 2H), 7.35 (d, J=7.7Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 4.48 (s, 2H), 3.53 (t, J=5.9 Hz, 2H),2.72 (t, J=5.8 Hz, 2H), 1.42 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−59.40-−62.27 (m), −125.03; MS (ES−): 527.7 (M−1).

Step-3: Preparation of tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161d)

To a stirred solution of tert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161c) (0.223 g, 0.421 mmol) in anhydrous methanol (10 mL), cooled to 0°C., was added di-tert-butyl dicarbonate [Boc anhydride] (0.184 g, 0.842mmol), nickel(II) chloride hexahydrate (0.020 g, 0.084 mmol), followedby the addition of sodium borohydride (0.159 g, 4.21 mmol) in smallportions over a period of 5 min. The reaction mixture was stirred for 15min at room temperature, quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.091 mL, 0.842 mmol), stirred for30 mins and concentrated in vacuum to dryness. The residue was treatedwith ethyl acetate (25 mL), washed with water (25 mL, brine (25 mL),dried over MgSO₄ and concentrated in vacuum. The residue was purified byflash column chromatography (silica gel 25 g, eluting with 0-20% ethylacetate in hexanes) to afford tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161d) (98 mg, 37% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.56 (s, 1H, D₂O exchangeable), 7.58 (s, 1H), 7.49 (dd, J=14.5, 7.5 Hz,1H), 7.41 (d, J=8.6 Hz, 2H), 7.35 (t, J=6.2 Hz, 2H), 7.17 (d, J=11.1 Hz,1H), 4.47 (s, 2H), 4.19 (d, J=6.4 Hz, 2H), 3.52 (t, J=5.8 Hz, 2H), 2.72(t, J=5.6 Hz, 2H), 1.41 (s, 9H), 1.38 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.82, −125.28; MS (ES⁺): MS (ES+) 656.3 (M+Na), MS (ES−)632.4 (M−1). Analysis calculated for: C₃₁H₃₅F₄N₅O₅: C, 58.76; H, 5.57;N, 11.05; Found: C, 58.65; H, 5.86; N, 10.69.

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(161e)

To a solution of tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(161d) (0.086 g, 0.136 mmol) in dioxane (4 mL), was added hydrogenchloride (4M in dioxane, 1.9 mL, 7.60 mmol) and stirred at roomtemperature for 14 h. The reaction mixture was diluted with hexanes,filtered, dried under vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(161e) (28 mg, 48% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.75 (s, 1H, D₂O exchangeable), 9.64 (s, 2H, D₂Oexchangeable), 8.47 (s, 3H, D₂O exchangeable), 7.72 (s, 2H), 7.67-7.61(m, 2H), 7.56 (s, 1H), 7.52 (m, 1H), 7.50-7.43 (m, 1H), 7.23 (d, J=11.0Hz, 1H), 4.22 (s, 2H), 4.12 (s, 2H), 3.35 (m, 2H), 2.97 (m, 2H); ¹H NMR(300 MHz, DMSO-d₆ D₂O) δ 7.71 (s, 1H), 7.67 (m, 1H), 7.60 (m, 1H),7.58-7.45 (m, 3H), 7.23 (d, J=11.0 Hz, 1H), 4.25 (s, 2H), 4.12 (s, 2H),3.39-3.31 (m, 2H), 2.98 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82,−124.02; MS (ES⁺): MS (ES+) 434 (M+1), (ES−) 431.8 (M−1); Analysiscalculated for C₂₁H₁₉F₄N₅O.2.25HCl.3H₂O: C, 44.29; H, 4.82; N, 12.30;Found: C, 44.29; H, 4.82; N, 12.30.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(162c) Step-1: Preparation of tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(162b)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (58.0 mg, 0.151 mmol) in DMF (1.4 mL) was added tert-butyl6-amino-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (162a) (40mg, 0.150 mmol) (prepared according to procedure reported in literature(a) Watson, Nigel S. et al; Bioorganic & Medicinal Chemistry Letters,21(6), 1588-1592; 2011 (b) Preparation of3-sulfonvlaminopyrrolidin-2-ones as factor Xa inhibitors. Harling, JohnDavid et al; WO 2006/108709, 19 Oct. 2006),N-ethyl-N-isopropylpropan-2-amine (0.210 mL, 1.206 mmol) andbromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (72.0 mg,0.151 mmol) and stirred at room temperature for 14 h. The reactionmixture was diluted with ethyl acetate (75 mL), washed with water (2×30mL), brine (30 mL), and dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel 4 g, eluting with hexanes/ethyl acetate (1:0to 2:1)] to give tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(162b) (49 mg, 52%) as a colorless film; ¹H NMR (300 MHz, CDCl₃) δ 7.95(s, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.53-7.33 (m, 5H), 7.16 (s, 1H), 6.86(d, J=8.5 Hz, 1H), 4.53 (s, 2H), 4.37 (d, J=6.1 Hz, 2H), 3.63 (t, J=5.9Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 1.48 (s, 9H), 1.43 (s, 9H); MS (ES+):655.9 (M+23).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(162c)

To a solution of tert-butyl6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(162b) (48 mg, 0.076 mmol) in 1,4-Dioxane (5 mL) was added hydrogenchloride (1.100 mL, 4.40 mmol, 4 M in 1,4-dioxane) and stirred at roomtemperature for 17 h. The reaction mixture was treated with hexanes,filtered, washed with hexanes. The insoluble crude product was purifiedby flash column chromatography [silica gel 4 g, eluting withchloroform/CMA80 (1:0 to 1:1)] to give1-(3-(aminomethyl)phenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(27.5 mg, 84%) as a white solid; ¹HNMR (300 MHz, Methanol-d4) δ7.58-7.28 (m, 6H), 6.88 (d, J=8.3 Hz, 1H), 3.93-3.89 (m, 2H), 3.85 (s,2H), 3.06 (t, J=6.1 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H); ¹⁹FNMR (282 MHz,Methanol-d₄) δ −63.69, −130.74; MS (ES+): 434.08 (M+H).

Preparation of1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(163g) Step-1: Preparation of6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (163b)

A cold solution of potassium nitroperoxous acid (4.50 g, 44.5 mmol) inConc. sulfuric acid (22 mL) was added6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (163a) (prepared according tothe literature: Kurouchi, H.; Kawamoto, K.; Sugimoto, H.; Nakamura, S.Otani, Y.; Ohwada, T. Journal of Organic Chemistry (2012), 77(20),9313-9328) (5.45 g, 33.0 mmol) was added drop-wise over a period of tenminutes. The reaction stirred for 17 h at room temperature, thensolution was poured on to a mixture of 104 g ice and 120 mL water. Theprecipitate was collected by filtration, washed with cold water (300 mL)and dried under reduced pressure over P205 to afford6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (163b) (6.42 g, 93%yield) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=7.9Hz, 1H), 8.33 (s, 1H), 7.64 (d, J=11.8 Hz, 1H), 3.43 (td, J=6.6, 2.9 Hz,2H), 3.04 (t, J=6.6 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −114.89; MS(ES⁺): MS (ES+) 211.1 (M+1), 233.1 (M+Na), 443.3 (2M+Na), MS (ES−) 209.1(M−1). Analysis calculated for C₉H₇FN₂O₃: C, 51.43; H, 3.36; N, 13.33;Found: C, 51.27; H, 3.27; N, 13.14.

Step-2: Preparation of 7-amino-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one(163c)

To a solution of 6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one(163b) (1.86 g, 8.85 mmol) in methanol (20 mL) was added palladium oncarbon (10%) (0.471 g, 4.43 mmol) and hydrogenated at 60 Psi for 3 h.The catalyst was removed by filtration through Celite and the filtratewas concentrated in vacuum. The residue was purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate/methanol(9:1) in hexanes from 0-100%] to furnish7-amino-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (163c) (1.011 g, 63%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.84-7.65 (m, 1H),7.30 (d, J=9.4 Hz, 1H), 6.94 (d, J=11.6 Hz, 1H), 5.17 (s, 2H, D₂Oexchangeable), 3.33-3.26 (m, 2H), 2.71 (t, J=6.6 Hz, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −130.21; MS (ES⁺): MS (ES+) 181.2 (M+1), 360.08 (2M+1),383.01 (2M+1).

Step-3: Preparation of 6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-amine(163d)

A suspension of 7-amino-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (163c)(0.8 g, 4.44 mmol) in THF (30 mL) was treated with lithium aluminumhydride (22.20 mL, 22.20 mmol) (1 M in THF) at room temperature followedby reflux for 15 h. TLC analysis show reaction was incomplete, thencooled to room temperature, and added a additional lithium aluminumhydride (22.20 mL, 22.20 mmol) at room temperature followed by refluxfor 16 h, cooled to room temperature and very carefully treated with aq.20% Na₂SO₄ (30 mL) over a period of 10 min at 10-15° C. followed bydilution with CMA50 (150 mL), filtered through Celite, washed with CMA50(50 mL), methanol (50 mL), filtrate was evaporated to dryness. Theresidue was purified by flash column chromatography (40 g silica gel,eluting with CMA80 in chloroform from 0-100%) to furnish6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-amine (163d) (0.557 g, 3.35mmol, 75% yield) as a white solid, which used as such in next step; MS(ES⁺): MS (ES+) 167.3 (M+1).

Step-4: tert-butyl7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e)

A solution of 6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-amine (163d) (532mg, 3.20 mmol) in dichloromethane (20 mL) and MeOH (10 mL) was treatedwith di-tert-butyl dicarbonate (0.710 g, 3.22 mmol) and triethylamine(TEA; 0.892 mL, 6.40 mmol) drop-wise followed by stirring at roomtemperature for 12 h. Excess solvent was pumped-off, extracted withchloroform (2×75 mL), washed with water (50 mL), dried over MgSO₄followed by filtration and concentration. The crude residue and waspurified by flash column chromatography (25 g silica gel, ethyl acetatein hexanes from 0-100%) to furnish tert-butyl7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e) (0.289g, 1.085 mmol, 33.9% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 6.77 (d, J=12.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 4.96 (s, 2H, D₂Oexchangeable), 4.31 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.59 (t, J=5.9 Hz,2H), 1.41 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.46; Analysiscalculated for C₁₄H₁₉FN₂O₂: C, 63.14; H, 7.19; N, 10.52; Found: C,63.13; H, 7.23; N, 10.47.

Step-5: Preparation of tert-butyl7-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(163f)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (150 mg, 0.389 mmol) in N,N-dimethylformamide (2.5 mL) wasadded tert-butyl7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e) (104mg, 0.389 mmol), N-ethyl-N-isopropylpropan-2-amine (0.542 mL, 3.11 mmol)and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBroP)(0.218 g, 0.467 mmol) at room temperature. The resulting reactionmixture was stirred at 25° C. for 16 h. Excess DMF was completelyremoved under reduced pressure, reaction mixture was diluted with water(30 mL), and extracted with ethyl acetate (50 mL, 25 mL). The organiclayers were combined dried over anhydrous MgSO₄, filtered, andconcentrated in vacuum to dryness. The residue was purified by flashcolumn chromatography (silica gel 25 g, eluting with hexanes in ethylacetate/hexanes from 0-100%) to furnish product tert-butyl7-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(163f) (116 mg, 47% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.56 (s, 1H), 7.58 (s, 1H), 7.42 (m, 6H), 7.12 (d, J=11.0 Hz, 1H), 4.45(s, 2H), 4.19 (s, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.75 (t, J=6.0 Hz, 2H),1.42 (s, 9H), 1.37 (s, 9H); MS (ES⁺): MS (ES+) 656.0 (M+Na), (ES−) 631.7(M−1); Analysis calculated for C₃₁H₃₅F₄N₅O₅: C, 58.76; H, 5.57; N,11.05; Found: C, 58.65; H, 5.65; N, 10.75.

Step-6: Preparation of1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(163g)

To a solution of tert-butyl7-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(163f) (95 mg, 0.150 mmol) in dioxane (4 mL) was added hydrogen chloride(4M in dioxane) (2.099 mL, 8.40 mmol) and stirred at room temperaturefor 14 h. The reaction mixture was diluted with hexanes, filtered, driedunder vacuum to furnish1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(163g) (46 mg, 71% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.75 (s, 1H, D₂O exchangeable), 9.61 (s, 2H, D₂Oexchangeable), 8.48 (s, 2H, D₂O exchangeable), 7.72 (s, 2H), 7.67-7.43(m, 4H), 7.21 (d, J=11.0 Hz, 1H), 4.20 (s, 2H), 4.16-4.07 (m, 2H), 3.33(d, J=6.0 Hz, 2H), 3.00 (d, J=6.3 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆-D₂O)δ 7.71 (s, 1H), 7.67 (s, 1H), 7.64-7.44 (m, 4H), 7.23 (d, J=11.0 Hz,1H), 4.22 (s, 2H), 4.12 (s, 2H), 3.36 (t, J=6.1 Hz, 2H), 3.00 (t, J=6.3Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −123.09; MS (ES⁺): MS(ES+) 434.0 (M+1), (ES−) 431.7 (M−1); Analysis calculated forC₂₁H₁₉F₄N₅O.2HCl 1.25H₂O: C, 47.69; H, 4.48; Cl, 13.41; N, 13.24; Found:C, 47.39; H, 4.23; Cl, 13.78; N, 13.84.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164e) Step-1: Preparation of tert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(164a)

A solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(180 mg, 0.640 mmol) in DMF (6 mL) was treated with tert-butyl6-amino-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (162a) (170mg, 0.638 mmol), N-ethyl-N-isopropylpropan-2-amine (0.890 mL, 5.11 mmol)and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (PyBrOP,306 mg, 0.643 mmol) followed by stirring at RT for 15 h. The reactionmixture was diluted with ethyl acetate (150 mL), washed with water (2×75mL) and brine (75 mL), and dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel 4 g, eluting with hexanes/ethyl acetate (1:0to 2:1)] to give tert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(164a) (166 mg, 49%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H), 8.16-8.10 (m, 1H), 8.02-7.98 (m, 1H), 7.90 (ddd, J=8.1,2.1, 1.1 Hz, 1H), 7.76-7.70 (m, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.04 (d,J=8.3 Hz, 1H), 4.51 (s, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.73 (t, J=5.8 Hz,2H), 1.42 (s, 9H); MS (ES+): 552.2 (M+23).

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164b)

A solution of tert-butyl6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(164a) (100 mg, 0.189 mmol) in 1,4-Dioxane (10 mL) was treated withhydrogen chloride (2.0 mL, 8.00 mmol, 4 M in 1,4-dioxane) and stirred atRT for 17 h. The reaction mixture was treated with hexanes, decanted,washed with hexanes, and decanted again. The insoluble crude product waspurified by flash column chromatography [silica gel, eluting withchloroform/CMA 80 (1:0 to 2:1)] to give1-(3-cyanophenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164b) (74 mg, 91%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.48(s, 1H), 8.14-8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.93-7.87 (m,1H), 7.80-7.67 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H),3.82 (s, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.97, −127.51; MS (ES+): 430.2 (M+1).

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164c)

A solution of1-(3-cyanophenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164b) (35 mg, 0.082 mmol) in formic acid (0.3 mL) was treated withformaldehyde (7.00 μL, 0.094 mmol) followed by stirring at 70° C. for 6h. The reaction mixture was concentrated to dryness. The residue wastreated with ethanol followed by concentration again (this process wasrepeated two more times). The crude product was purified by flash columnchromatography [silica gel, eluting with chloroform/CMA 80 (1:0 to 4:1)]to give1-(3-cyanophenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164c) (34 mg, 94%) as a light yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.50 (s, 1H), 8.16-7.68 (m, 5H), 7.29 (t, J=7.9 Hz, 1H), 6.92 (d, J=8.2Hz, 1H), 3.49 (s, 2H), 2.75 (t, 2H), 2.62 (t, 2H), 2.35 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.98, −126.90; MS (ES+): 444.2 (M+1).

Step-4: Preparation of tert-butyl3-(5-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(164d)

To a solution of1-(3-cyanophenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164c) (30 mg, 0.068 mmol) in MeOH (2 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (45.0 mg, 0.204 mmol), nickel(II)chloride hexahydrate (4.0 mg, 0.017 mmol) followed by portionwiseaddition of sodium borohydride (16.00 mg, 0.414 mmol) and stirred at RTfor 1 h. The reaction mixture was treatedN1-(2-aminoethyl)ethane-1,2-diamine (0.015 mL, 0.140 mmol) followed bystirring at RT for 0.5 h and concentration to dryness. The residue wastreated with chloroform (120 mL), washed with water (60 mL). The aqueousphase was extracted again with chloroform (60 mL). The combined extractswere dried over MgSO₄ followed by filtration and concentration. Thecrude product was purified by flash column chromatography [silica gel,eluting with chloroform/methanol (1:0 to 19:1)] to give tert-butyl3-(5-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(164d) (13 mg, 35%) as a colorless foam; ¹H NMR (300 MHz, Methanol-d₄) δ7.55-7.28 (m, 6H), 6.95-6.86 (m, 1H), 4.29 (s, 2H), 3.59 (s, 2H), 2.89(dt, J=7.1, 3.6 Hz, 2H), 2.74 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 1.42 (s,9H); ¹⁹F NMR (282 MHz, Methanol-d₄) δ −63.71, −130.50; MS (ES+): 548.3(M+1).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(164e)

A solution of tert-butyl3-(5-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(164d) (13 mg, 0.024 mmol) in 1,4-Dioxane (2 mL) was treated withhydrogen chloride (0.250 mL, 1.002 mmol, 4 M in 1,4-dioxane) followed bystirring at RT for 14 h. The reaction mixture was treated with hexanes,decanted, washed with hexanes, and decanted again. The insoluble crudeproduct was purified by flash column chromatography [silica gel 4 g,eluting with chloroform/CMA 80 (1:0 to 1:2)] to give (3.9 mg, 37%) as alight yellow gum; ¹H NMR (300 MHz, Methanol-d₄) δ 7.55-7.28 (m, 6H),6.95-6.86 (m, 1H), 4.29 (s, 2H), 3.59 (s, 2H), 2.89 (dt, J=7.1, 3.6 Hz,2H), 2.74 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 1.42 (s, 9H); ¹⁹F NMR (282MHz, Methanol-d₄) δ −63.71, −130.50; MS (ES+): 448.09 (M+1).

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165e) Step-1: Preparation of (−)-(3-nitrophenyl)(phenyl)methanol (165a)

To a cold [(−40° C. (acetonitrile/dry ice)] stirred solution of(3-nitrophenyl)(phenyl)methanone (18a) (4 g, 17.60 mmol) in THF (150 mL)was added(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4.40mL, 4.40 mmol) drop-wise and stirred at room temperature for 1 h in apositive flow of nitrogen then borane-methyl sulfide complex (17.60 mL,35.2 mmol) was added slowly in a positive flow of nitrogen over a periodof 1 h. The reaction was stirred at −40° C. for 2 h. TLC analysis showsreaction was complete. Reaction mixture was carefully quenched with 60mL methanol at −40° C. and stirred for 12 h at room temperature, andthen the reaction mixture was treated with silica gel, prepared theslurry under reduced pressure. The residue was purified by flash columnchromatography [(silica gel 120 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish (−)-(3-nitrophenyl)(phenyl)methanol (165a)(3.808 g, 94% yield) as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.25 (t, J=2.0 Hz, 1H), 8.09 (ddd, J=8.2, 2.5, 1.1 Hz, 1H), 7.86-7.78(m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.45-7.39 (m, 2H), 7.37-7.29 (m, 2H),7.28-7.20 (m, 1H), 6.25 (d, J=4.1 Hz, 1H), 5.88 (d, J=4.1 Hz, 1H); MS(ES−) 457.3 (2M−1); Optical rotation: [α]_(D)=(−) 40.65 [CHCl₃, 1.23].

-   Lit: For absolute stereochemistry, see, Truppo, M.; Morley, K.;    Pollard, D.; Devine, P.; Edited by Whittall, J.; Sutton, P.;    Practical Methods for Biocatalysis and Biotransformations (2010),    288-290.

Step-2: Preparation of(−)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b)

To a stirred solution of (−)-(3-nitrophenyl)(phenyl)methanol (165a) (3.8g, 16.58 mmol) in THF (60 mL) at 0° C. was added KHMDS (0.5M in toluene)(39.8 mL, 19.89 mmol) (bromomethyl)cyclopropane (6.43 mL, 66.3 mmol) andstirred at 0° C. for 3 h in a positive flow of nitrogen. TLC analysis(ethyl acetate/hexanes, 2/8, v/v) shows complete conversion. Thereaction was carefully quenched with sat. NH₄Cl (100 mL), and extractedwith ethyl acetate (2×100 mL), combined organics were dried overanhydrous MgSO₄, filtered, evaporated to dryness. The residue waspurified by flash column chromatography [(silica gel 40 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish(−)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b) (0.224g, 5% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (t, J=2.0Hz, 1H), 8.05 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.76 (dt, J=7.7, 1.3 Hz,1H), 7.57 (t, J=7.9 Hz, 1H), 7.40-7.17 (m, 5H), 5.63 (s, 1H), 3.21 (d,J=6.8 Hz, 2H), 1.02 (dddd, J=10.0, 6.7, 4.0, 1.6 Hz, 1H), 0.41 (ddd,J=8.0, 3.9, 2.0 Hz, 2H), 0.10 (ddd, J=6.0, 4.7, 3.2 Hz, 2H); Opticalrotation: [α]_(D)=(−) 28.57 [CHCl₃, 1.905].

Step-3: Preparation of (−)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline(165c)

To a stirred solution of(−)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b) (0.211g, 0.745 mmol) in anhydrous methanol (30 mL), cooled to 0° C., was addednickel(II) chloride hexahydrate (0.089 g, 0.372 mmol) followed by sodiumborohydride (0.169 g, 4.47 mmol) in small portions over a period of 5min. The reaction mixture was stirred for 15 min at 0° C. TLC analysis(ethyl acetate/hexanes, 2/8, v/v) shows reaction was complete at thispoint N1-(2-aminoethyl)ethane-1,2-diamine (0.805 mL, 7.45 mmol) wasadded. The mixture was allowed to stir for 30 minutes more beforesolvent evaporated. The residue was treated sat NH₄Cl (25 mL), andextracted with ethyl acetate (2×25 mL). Organic layer was dried overanhydrous MgSO₄, filtered, and excess solvents were pumped-off underreduced pressure. The residue was purified by flash columnchromatography [(silica gel 25 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish(−)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (165c) (0.141 g, 75%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.23-7.12 (m, 4H),7.09-7.00 (m, 1H), 6.78 (t, J=7.7 Hz, 1H), 6.42 (t, J=1.9 Hz, 1H), 6.34(dt, J=7.5, 1.3 Hz, 1H), 6.25 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.10 (s,1H), 4.90 (s, 2H, D₂O exchangeable), 3.14-2.98 (m, 2H), 1.01-0.80 (m,1H), 0.40-0.25 (m, 2H), 0.06-−0.07 (m, 2H); MS (ES+) 254.2 (M+1), 276.2(M+Na); Optical rotation: [α]_(D)=(−) 5.68 [CHCl₃, 1.055].

Step-4: Preparation of(−)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165d)

A single-necked 100 mL flask was charged with1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.210 g, 0.746 mmol), (−)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline(165c) (0.126 g, 0.497 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 0.278 g, 0.597 mmol) was addedN,N-dimethylformamide (6 mL) and N-ethyl-N-isopropylpropan-2-amine(0.433 mL, 2.487 mmol) successively in a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 12 h under a positive flow of nitrogen atmosphere.Excess DMF was pumped-off under reduced pressure. The residue wastreated with sat. NH₄Cl solution (30 mL), and extracted with ethylacetate (2×50 mL) combined organics were dried over anhydrous MgSO₄,filtered, evaporated to dryness. The residue was then purified by flashcolumn chromatography [silica gel 40 g, eluting with ethyl acetate inhexanes from 0-100%] to furnish(−)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165d) (0.234 g, 91% yield) as a colorless waxy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.68 (s, 1H, D₂O exchangeable), 8.17 (t, J=1.8 Hz, 1H), 8.00(dt, J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79-7.69(m, 2H), 7.67-7.56 (m, 2H), 7.40-7.19 (m, 6H), 7.14 (dt, J=7.6, 1.3 Hz,1H), 5.45 (s, 1H), 3.24 (d, J=6.7 Hz, 2H), 1.06 (m, 1H), 0.55-0.38 (m,2H), 0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS (ES⁺): MS(ES+) 517.3 (M+1), 539.2 (M+Cl), MS (ES−) 515.2 (M−1); Optical rotation:Optical rotation: [α]_(D)=(−) 1.24 [CHCl₃, 1.285].

Step-5: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165e)

To a stirred solution of(−)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165d) (0.183 g, 0.354 mmol) in anhydrous methanol (30 mL) cooled to 0°C., was added nickel(II) chloride hexahydrate (0.105 g, 0.443 mmol)followed by sodium borohydride (0.107 g, 2.83 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 min, TLCanalysis (methanol/chloroform, 1/9, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (0.383 mL, 3.54 mmol) wasadded. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with sat. NH₄Cl (30 mL), and product wasextracted with chloroform (2×30 mL), combined organic layer was driedover MgSO₄, filtered, evaporated to dryness. The residue was purified byflash column chromatography [(silica gel 40 g, eluting withmethanol/chloroform from 0 to 50%)] to furnish(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(165e) (122 mg, 66% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H, D₂O exchangeable), 7.63 (t, J=1.9 Hz, 1H), 7.60-7.50 (m,3H), 7.47-7.39 (m, 2H), 7.37-7.20 (m, 7H), 7.13 (dt, J=7.6, 1.3 Hz, 1H),5.44 (s, 1H), 3.79 (s, 2H), 3.23 (dd, J=6.7, 1.4 Hz, 2H), 2.73 (s, 2H,D₂O exchangeable), 1.15-0.97 (m, 1H), 0.46 (ddd, J=8.5, 3.2, 2.1 Hz,2H), 0.15 (dt, J=4.2, 3.1 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.72;MS (ES⁺): MS (ES+) 521.3 (M+1), MS (ES−) 519.3 (M−1); Chiral HPLC:59.69% ee determined by HPLC with a Chiralpak AD-H column(isopropanol/hexanes=80:20, 0.8 mL/min, eluting with 0.1% triethylamine, uv 250 nM): Rt=6.58 min (minor), Rt=5.90 min (major); Opticalrotation: [α]_(D)=(−) 2.64 [CHCl₃, 1.06]; Analysis calculated forC₂₉H₂₇F₃N₄O₂.0.5H₂O: C, 65.77; H, 5.33; N, 10.58; Found: C, 65.81; H,5.30; N, 10.70.

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166e) Step-1: Preparation of (+)-(3-nitrophenyl)(phenyl)methanol (166a)

To a stirred solution of (3-nitrophenyl)(phenyl)methanone (18a) (3.95 g,17.38 mmol) in THF (60 mL) cooled to −40° C. (acetonitrile/dry ice)under a positive flow of nitrogen was added(S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4.35mL, 4.35 mmol) and stirred for 1 h, then borane-methyl sulfide complex(17.38 mL, 34.8 mmol) was added slowly under a positive flow ofnitrogen. The reaction was stirred at −40° C. for 3 h. TLC analysisshows reaction was complete. Reaction mixture was carefully quenchedwith 60 mL of methanol at 0° C. and stirred for 12 h at roomtemperature, and then the reaction mixture was treated with silica gel,prepared the slurry under reduced pressure. The residue was purified byflash column chromatography [(silica gel 120 g, eluting with ethylacetate/hexanes from 0 to 50%)] to furnish(+)-(3-nitrophenyl)(phenyl)methanol (166a) (3.73 g, 94% yield) as ayellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (t, J=2.0 Hz, 1H), 8.08(ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.82 (ddt, J=7.7, 1.6, 0.8 Hz, 1H), 7.61(t, J=7.9 Hz, 1H), 7.46-7.39 (m, 2H), 7.37-7.29 (m, 2H), 7.28-7.20 (m,1H), 6.25 (d, J=4.1 Hz, 1H, D₂O exchangeable), 5.88 (d, J=4.1 Hz, 1H);Optical rotation: [α]_(D)=(+) 45.97 [CHCl₃, 1.34].

Step-2: Preparation of(+)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b)

To a stirred solution of (+)-(3-nitrophenyl)(phenyl)methanol (166a)(1.885 g, 8.22 mmol) in THF (60 mL) at 0° C. was added KHMDS (0.5M intoluene) (19.74 mL, 9.87 mmol), (bromomethyl)cyclopropane (3.19 mL, 32.9mmol) and stirred at 0° C. for 3h under a positive flow of nitrogen. TLCanalysis (ethyl acetate/hexanes, 2/8, v/v) shows complete conversion.The reaction was carefully quenched with sat. NH₄Cl (60 mL), andextracted with ethyl acetate (2×60 mL), combined organics were driedover anhydrous MgSO₄, filtered, evaporated to dryness. The residue waspurified by flash column chromatography [(silica gel 40 g, eluting withethyl acetate/hexanes from 0 to 50%)] to furnish(+)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b) (137mg, 6% yield) as a clear oil; ¹H NMR (300 MHz, Chloroform-d) δ 8.27 (t,J=1.9 Hz, 1H), 8.10 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.68 (ddt, J=7.8,1.6, 0.8 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.36 (d, J=4.3 Hz, 4H),7.33-7.28 (m, 1H), 5.48 (s, 1H), 3.33 (d, J=6.8 Hz, 2H), 1.13 (dddd,J=13.3, 6.8, 5.0, 2.6 Hz, 1H), 0.67-0.46 (m, 2H), 0.29-0.12 (m, 2H); MS(ES+) 306.2 (M+Na); Optical rotation: [α]_(D)=(+) 36.07 [CHCl₃, 0.755].

Step-3: Preparation of (+)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline(166c)

To a stirred solution of(−)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b) (133mg, 0.469 mmol) in anhydrous methanol (30 mL), cooled to 0° C., wasadded nickel(II) chloride hexahydrate (0.056 g, 0.235 mmol) followed bysodium borohydride (0.107 g, 2.82 mmol) small portions over a period of5 min. The reaction mixture was stirred for 23 min at 0° C. TLC analysis(ethyl acetate/hexanes, 5/95, v/v) shows reaction was complete at thispoint N1-(2-aminoethyl)ethane-1,2-diamine (0.507 mL, 4.69 mmol) wasadded. The mixture was allowed to stir for 30 minutes before solvent wasevaporated. The residue was treated sat NH₄Cl (25 mL), and extractedwith ethyl acetate (2×25 mL). Organic layer were combined dried overanhydrous MgSO₄, filtered, and excess solvents were pumped-off underreduced pressure. The residue was purified by flash columnchromatography [(silica gel 12 g, eluting with ethyl acetate/hexanesfrom 0 to 50%)] to furnish(+)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (166c) (101 mg, 85%yield) as a yellow solid; ¹H NMR (300 MHz, Chloroform-d) δ 7.38-7.30 (m,3H), 7.29-7.21 (m, 2H), 7.09 (t, J=7.7 Hz, 1H), 6.79-6.69 (m, 2H), 6.56(ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.31 (s, 1H), 3.31 (dd, J=6.8, 3.1 Hz,2H), 1.12 (ttt, J=8.0, 6.7, 4.8 Hz, 1H), 0.62-0.45 (m, 2H), 0.18 (dt,J=6.0, 4.4 Hz, 2H); MS (ES⁺): MS (ES+) 254.2 (M+1), 276.2 (M+Na), MS(ES−) 515.2 (M−1); Optical rotation: [α]_(D)=(+) 6.868 [CHCl₃, 1.19].

Step-4: Preparation of(+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166d)

A single-necked 100 mL flask containing1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(155 mg, 0.551 mmol), (+)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline(166c) (0.093 g, 0.367 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrOP, 0.205 g, 0.441 mmol) was addedN,N-dimethylformamide (4.26 mL) and N-ethyl-N-isopropylpropan-2-amine(0.320 mL, 1.835 mmol) successively under a positive flow of nitrogen atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 16 h under a positive flow of nitrogen atmosphere.Excess DMF was pumped-off under reduced pressure. The residue wastreated with water (30 mL), and extracted with chloroform (2×50 mL).Combined organics were dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue was then purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-50%] to furnish(+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166d) (172 mg, 91% yield) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H, D₂O exchangeable), 8.17 (t,J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.3, 1.2Hz, 1H), 7.81-7.69 (m, 2H), 7.68-7.55 (m, 2H), 7.46-7.21 (m, 6H),7.18-7.09 (m, 1H), 5.45 (s, 1H), 3.23 (d, J=6.8 Hz, 2H), 1.12-0.99 (m,1H), 0.57-0.40 (m, 2H), 0.15 (tdd, J=4.2, 2.6, 1.6 Hz, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.96; MS (ES⁺): MS (ES+) 539.3 (M+1), MS (ES−) 515.2(M−1); Optical rotation: [α]_(D)=(+) 0.84 [CHCl₃, 0.955].

Step-5: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a stirred solution of(+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166e)

To a solution of(+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166d) (0.151 g, 0.292 mmol) in anhydrous methanol (30 mL) cooled to 0°C., was added nickel(II) chloride hexahydrate (0.087 g, 0.365 mmol)followed by sodium borohydride (0.088 g, 2.339 mmol) in small portionsover a period of 5 min. The reaction mixture was stirred for 10 min, TLCanalysis (methanol/chloroform, 1/9, v/v) shows reaction was complete atthis point N1-(2-aminoethyl)ethane-1,2-diamine (0.316 mL, 2.92 mmol) wasadded. Excess methanol was pumped-off under reduced pressure. Thereaction mixture was treated with sat. NH₄Cl (30 mL), and product wasextracted with chloroform (2×30 mL), combined organic layer was driedover MgSO₄, filtered, evaporated to dryness. The residue was purified byflash column chromatography [(silica gel 25 g, eluting withmethanol/chloroform from 0 to 50%)] to furnish(+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(166e) (107 mg, 70% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H, D₂O exchangeable), 7.63 (t, J=1.8 Hz, 1H), 7.60-7.50 (m,3H), 7.42 (d, J=6.6 Hz, 2H), 7.37-7.20 (m, 7H), 7.16-7.10 (m, 1H), 5.44(s, 1H), 3.77 (s, 2H), 3.23 (dd, J=6.8, 1.3 Hz, 2H), 1.05 (m, 1H), 0.46(dq, J=8.5, 3.5, 2.6 Hz, 2H), 0.19-0.09 (m, 2H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.72. MS (ES⁺): MS (ES+) 521.3 (M+1), MS (ES−) 519.3 (M−1);Chiral HPLC: 72.95% ee determined by HPLC with a Chiralpak AD-H column(isopropanol/hexanes=20:80, 0.8 mL/min, eluting with 0.1% triethylamine, uv 250 nM): Rt=5.97 min (minor), Rt=6.52 min (major). Opticalrotation: [α]_(D)=(+) 3.018 [CHCl₃, 1.06]; Analysis calculated forC₂₉H₂₇F₃N₄O₂.0.25H₂O: C, 66.34; H, 5.28; N, 10.67; Found: C, 66.23; H,5.30; N, 10.38.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167f) Step-1: Preparation of (3-aminophenyl)(2-nitrophenyl)methanol(167b)

To a solution of 2-nitrobenzaldehyde (167a) (4.63 g, 30 mmol) intetrahydrofuran (30 mL) cooled to 0° C. was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (36.0 mL,36.0 mmol) and stirred at room temperature for 12 h. The reactionmixture was treated with 1 N HCl (aq. 75 mL), stirred at roomtemperature for 3 h, neutralized with NaOH (2 N, aq.) to pH=˜8, andextracted with ethyl acetate (2×100 mL). The combined extracts werewashed with brine (80 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography [silica gel 120 g, eluting with chloroform/methanol (1:0to 19:1)] to give (3-aminophenyl)(2-nitrophenyl)methanol (167b) (3.76 g,51%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.87-7.82 (m, 1H), 7.77-7.67 (m, 2H),7.50 (ddd, J=8.0, 6.6, 2.2 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.46 (t,J=1.9 Hz, 1H), 6.41 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 6.36 (dt, J=7.6, 1.3Hz, 1H), 6.05 (s, 2H), 5.04 (s, 2H); MS (ES+): 267.2 (M+Na).

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(hydroxy(2-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167c)

A solution of (3-aminophenyl)(2-nitrophenyl)methanol (167b) (3.6 g,14.74 mmol) in DMF (75 mL) was treated with1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(4.14 g, 14.74 mmol), N-ethyl-N-isopropylpropan-2-amine (21.00 mL, 121mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate(V)(PyBrOP, 7.01 g, 14.74 mmol) followed by stirring at RT for 16 h. Thereaction mixture was diluted with ethyl acetate (400 mL), washed withwater (2×120 mL) and brine (120 mL), and dried over MgSO₄ followed byfiltration and concentration. The crude product was purified by flashcolumn chromatography [silica gel 120 g, eluting with hexanes/ethylacetate (1:0 to 1:1)] to give1-(3-cyanophenyl)-N-(3-(hydroxy(2-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167c) (3.45 g, 46%) yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s,1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.93-7.87 (m,2H), 7.78-7.69 (m, 4H), 7.65-7.49 (m, 3H), 7.28 (t, J=7.9 Hz, 1H), 7.01(d, J=7.7 Hz, 1H), 6.30 (d, J=4.7 Hz, 1H), 6.18 (d, J=4.6 Hz, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.96; MS (ES+): 530.2 (M+Na).

Step-3: Preparation of tert-butyl3-(5-((3-((2-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167d)

A solution of1-(3-cyanophenyl)-N-(3-(hydroxy(2-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167c) (3.309 g, 6.52 mmol) in MeOH (110 mL) cooled with ice/water wasadded di-tert-butyl dicarbonate (5.75 g, 26.1 mmol), nickel(II) chloridehexahydrate (0.834 g, 3.51 mmol), followed by addition of SodiumBorohydride (2.52 g, 65.2 mmol) slowly over 5 min and stirring at RT for1 h. The reaction mixture was treatedN₁-(2-aminoethyl)ethane-1,2-diamine (3.30 mL, 30.3 mmol) followed bystirring at RT for 0.5 h and concentration to dryness. The residue wastreated with ethyl acetate (300 mL), washed with water (120 mL). Theaqueous phase was extracted again with ethyl acetate (150 mL). Thecombined extracts were washed with brine (150 mL), dried over MgSO₄followed by filtration and concentration. The crude product was purifiedby flash column chromatography [silica gel 80 g, eluting withhexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl3-(5-((3-((2-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167d) (975 mg, 22%) as a light yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.70 (s, 1H), 8.58 (s, 1H), 7.61 (s, 1H), 7.59-7.18 (m, 11H),7.08-7.00 (m, 2H), 6.49 (d, J=4.0 Hz, 1H), 5.88 (d, J=3.9 Hz, 1H), 4.19(d, J=6.2 Hz, 2H), 1.37 (s, 9H), 1.36 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.82; MS (ES+): 704.4 (M+Na).

Step-4: Preparation of tert-butyl3-(5-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167e)

A solution of tert-butyl3-(5-((3-((2-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167d) (970 mg, 1.402 mmol) in dichloromethane (28 mL) at 0° C. wastreated with thionyl chloride (0.220 mL, 2.97 mmol) and allowed to warmto room temperature over 2 h. The reaction mixture was treated withtriethyl amine (1.30 mL, 9.33 mmol) followed by stirring at RT for 1 h.It was then treated with cyclopropylmethanamine (2.70 mL, 30.2 mmol) andconcentrated to remove most of dichloromethane followed by addition ofacetonitrile (21 mL), stirring at 70° C. for 14 h, and concentration todryness. The residue was treated with chloroform (200 mL), washed withwater (100 mL), dried over MgSO₄ followed by filtration andconcentration. The crude product was purified by flash columnchromatography on 25 g of silica gel with hexanes/ethyl acetate (1:0 to1:1) to give tert-butyl 3-(5-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167e) (255 mg, 30%) off-white solid, ¹H NMR (300 MHz, DMSO-d₆) δ 10.83(s, 1H), 10.35 (s, 1H), 8.12-7.25 (m, 10H), 7.09 (d, J=7.6 Hz, 1H),7.04-6.87 (m, 3H), 6.53 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H);MS (ES+): 630.3 (M+Na).

Step-5: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167f)

A solution of tert-butyl3-(5-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(167e) (120 mg, 0.198 mmol) in 1,4-Dioxane (12 mL) was treated withhydrogen chloride (2.2 mL, 8.8 mmol, 4 M in 1,4-dioxane) slowly followedby stirring at RT for 14.5 h. The reaction mixture was treated withhexanes, decanted, washed with hexanes, and decanted again. Theinsoluble crude product was purified by flash column chromatography[silica gel with chloroform/CMA80 (1:0 to 1:1)]to give1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(167f) (33 mg) as a colorless gum as a free base; The purified product(167f) (31 mg, 33%) was dissolved in methanol (10 mL) and treated with 4N HCl (aq. 0.06 mL) followed by concentration to dryness to furnish1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d] [1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (33mg) hydrochloride salt as an off-white solid; ¹H NMR (D₂O ex NMR, 300MHz, DMSO-d₆) δ 7.73-7.49 (m, 7H), 7.42 (t, J=7.9 Hz, 1H), 7.35-7.27 (m,1H), 7.11 (d, J=7.7 Hz, 1H), 7.03 (td, J=7.5, 1.2 Hz, 1H), 6.97 (d,J=8.0 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.53 (s, 1H), 4.13 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.80; MS (ES+): 508.2 (M+H); IR (KBr pelletcm⁻¹): 3441, 3256, 1700, 1601, 1558, 1491, 1246; Analysis calculated forC₂₆H₂₀F₃N₅O₃.HCl.2.5H₂O: C, 53.02; H, 4.45; N, 11.89; Found: C, 53.22;H, 4.37; N, 11.33.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.16 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.5 g, 4.33 mmol) and stirred at room temperature for3 h. 2-amino-1-butanol (0.96 g, 10.81 mmol) was added and mixturestirred at room temperature for 30 min. The reaction mixture wasconcentrated in vacuum to dryness. The residue obtained was dissolved inacetonitrile (20 mL) and added 2-amino-1-butanol (0.964 g, 10.81 mmol).The reaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168a) (0.42 g, 36%) as an off white semi-solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (d, J=2.2 Hz, 1H), 8.15 (dd, J=2.1,1.2 Hz, 1H), 7.99 (dt, J=7.8, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1Hz, 1H), 7.76-7.71 (m, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.65 (d, J=14.3 Hz,1H), 7.58-7.51 (m, 1H), 7.40 (td, J=8.2, 1.4 Hz, 2H), 7.32-7.27 (m, 2H),7.26 (d, J=1.5 Hz, 1H), 7.24-7.19 (m, 2H), 4.96 (s, 1H), 4.48 (dt,J=6.5, 5.3 Hz, 1H), 3.56-3.40 (m, 1H), 3.34-3.27 (m, 1H), 2.34-2.26 (m,1H), 1.43-1.36 (m, 2H), 0.80 (dd, J=7.6, 1.7 Hz, 3H); MS (ES−) 532.8(M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168b)

To a solution of1-(3-cyanophenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168a) (0.42 g, 0.74 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.21 g, 0.89 mmol) and followedby portion-wise addition of Sodium Borohydride (0.16 g, 4.44 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.19 g,1.85 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 65 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168b) (0.2 g, 50%) as a yellow powder. This material was repurified byflash column chromatography (silica gel 12 g, eluting with methanol inchloroform) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(168b) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.80-10.57 (m,1H), 7.66 (dd, J=9.9, 2.2 Hz, 1H), 7.59-7.48 (m, 3H), 7.41 (dd, J=8.4,6.7 Hz, 4H), 7.35-7.13 (m, 6H), 4.96 (s, 1H), 3.77 (s, 2H), 3.49-3.30(m, 2H), 2.28 (q, J=5.5 Hz, 1H), 1.40 (p, J=7.1 Hz, 2H), 0.82 (t, J=7.4Hz, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −60.71; MS (ES+) 538-04 (M+1); (ES−)536.4 (M−1); Analysis calculated for C₂₉H₃₀F₃N₅O₂.0.5H₂O: C, 63.72; H,5.72; N, 12.81; Found: C, 64.02; H, 5.69; N, 12.63.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169b) Step-1:1-(3-cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.16 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Pyrrolidin-2-yl-methanol (1.093 g, 10.81 mmol) was added andstirred for 30 min. The reaction mixture was concentrated in vacuum todryness. The residue obtained was dissolved in acetonitrile (20 mL) andadded Pyrrolidin-2-yl-methanol (1.093 g, 10.81 mmol). The reactionmixture was heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (20 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-25% ethyl acetate inhexane) to afford1-(3-cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169a) (1.0 g, 83%) as a brownish oil; ¹H NMR (300 MHz, DMSO-d₆) δ 10.64(d, J=2.1 Hz, 1H), 8.20-8.12 (m, 1H), 8.00 (dq, J=7.7, 1.2 Hz, 1H), 7.90(ddt, J=8.2, 2.3, 1.3 Hz, 1H), 7.77-7.62 (m, 3H), 7.61-7.50 (m, 1H),7.41 (dd, J=8.0, 6.3 Hz, 2H), 7.31-7.17 (m, 5H), 4.73 (d, J=6.3 Hz, 1H),4.30 (dt, J=7.8, 5.3 Hz, 1H), 3.23-2.98 (m, 2H), 2.76 (ddd, J=22.8,10.8, 5.9 Hz, 2H), 2.37-2.20 (m, 1H), 1.81-1.59 (m, 4H); MS (ES−) 544.3(M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169b)

To a solution of1-(3-cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169a) (1.0 g, 1.834 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.547g, 2.303 mmol) and followedby portion-wise addition of sodium borohydride (0.416 g, 11.0 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.473g, 4.585 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(169b) (0.25 g, 25%) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 7.67 (d, J=16.9 Hz, 1H), 7.62-7.46 (m, 4H), 7.41 (td,J=7.4, 3.6 Hz, 3H), 7.24 (dddd, J=17.1, 10.8, 7.4, 3.2 Hz, 6H), 4.72 (d,J=5.7 Hz, 1H), 3.90 (s, 2H), 3.03 (dd, J=22.4, 9.8 Hz, 1H), 2.89-2.66(m, 2H), 2.33-2.21 (m, 2H), 1.69 (d, J=22.5 Hz, 4H); ¹⁹F NMR (282 MHz,DMSO) δ −60.73, −60.74; MS (ES+) 550.4 (M+1); (ES−) 548.4 (M−1) 584.4,(M+Cl); Analysis calculated for C₃₀H₃₀F₃N₅O₂.HCl.1.5H₂O: C, 58.77; H,5.59; N, 11.42; Found: C, 59.10; H, 5.54; N, 11.25.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.16 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Pyrrolidin-3-ol (0.94 g, 10.81 mmol) was added and stirred for30 min. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (20 mL) and addedPyrrolidin-3-ol (0.94 g, 10.81 mmol). The reaction mixture was heated atreflux overnight, cooled to room temperature and concentrated in vacuumto dryness. The residue was dissolved in dichloromethane (20 mL), washedwith water (2×25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting 0-25% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170a) (0.6 g, 52%) as a brownish oil; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65(s, 1H), 8.20-8.13 (m, 1H), 8.03-7.97 (m, 1H), 7.93-7.87 (m, 1H),7.78-7.66 (m, 3H), 7.56 (dt, J=7.1, 2.2 Hz, 1H), 7.46-7.42 (m, 1H), 7.41(s, 1H), 7.31-7.23 (m, 4H), 7.17 (t, J=7.2 Hz, 1H), 4.72 (dd, J=4.1, 2.4Hz, 1H), 4.25-4.14 (m, 2H), 2.59 (dt, J=11.0, 6.0 Hz, 1H), 2.45-2.15 (m,2H), 2.03 (d, J=8.0 Hz, 1H), 1.56 (d, J=8.7 Hz, 1H), 1.22 (d, J=1.9 Hz,1H); MS (ES−) 530.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170b)

To a solution of1-(3-cyanophenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170a) (0.6 gm 1.28 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.32 g, 1.35 mmol) and followedby portion-wise addition of Sodium Borohydride (0.25 g, 6.77 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.29 g,2.822 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(170b) (0.15 g, 22%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.75-10.66 (m, 1H), 7.68 (s, 1H), 7.66-7.60 (m, 2H), 7.52 (t, J=6.5 Hz,3H), 7.49-7.38 (m, 3H), 7.30-7.21 (m, 4H), 7.19 (d, J=7.3 Hz, 1H), 6.61(s, 2H), 4.71 (s, 1H), 4.20 (s, 2H), 4.00 (s, 2H), 2.66-2.58 (m, 1H),2.44 (dd, J=3.8, 1.9 Hz, 1H), 2.38-2.17 (m, 1H), 1.98 (dd, J=13.4, 6.8Hz, 1H), 1.56 (s, 1H); ¹⁹F NMR (282 MHz, DMSO) δ −60.76; MS (ES+) 536.4(M+1); (ES−) 535.1 (M−1); 570.4 (M+Cl); Analysis calculated forC₂₉H₂₈F₃N₅O₂.HCl.1.5H₂O: C, 58.14; H, 5.38; N, 11.69; Found: C, 58.37;H, 5.27; N, 11.82.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.16 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Cycloheptylamine (1.2 g, 10.81 mmol) was added and stirred for30 min. The reaction mixture was concentrated in vacuum to dryness. Theresidue obtained was dissolved in acetonitrile (20 mL) and addedCycloheptylamine (1.2 g, 10.81 mmol). The reaction mixture was heated atreflux overnight, cooled to room temperature and concentrated in vacuumto dryness. The residue was dissolved in dichloromethane (20 mL), washedwith water (2×25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting 0-25% ethyl acetate in hexane) to1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171a) (1.01 g, 84%) as a yellow powder; ¹H NMR (300 MHz, DMSO-d₆) δ10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7.8, 1.3 Hz, 1H),7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s,1H), 7.61 (t, J=1.7 Hz, 1H), 7.56-7.49 (m, 1H), 7.40-7.34 (m, 2H),7.32-7.21 (m, 3H), 7.21-7.13 (m, 2H), 4.89 (s, 1H), 2.48-2.38 (m, 1H),1.88-1.73 (m, 2H), 1.64-1.48 (m, 2H), 1.50-1.34 (m, 4H), 1.28-1.19 (m,4H); MS (ES−) 556.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171b)

To a solution of1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171a) (1.0 g, 1.783 mmol) in MeOH (25 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.532 g, 2.241 mmol) and followedby portion-wise addition of Sodium Borohydride (0.406 g, 10.758 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.739 g, 7.172 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(171b) (0.41 g, 41%) as a Off white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 7.63-7.54 (m, 4H), 7.55-7.48(m, 1H), 7.50-7.39 (m, 2H), 7.42-7.31 (m, 3H), 7.31-7.23 (m, 2H),7.25-7.09 (m, 2H), 4.88 (s, 1H), 3.87 (s, 2H), 2.43 (dd, J=3.7, 1.7 Hz,1H), 1.79 (s, 2H), 1.66-1.49 (m, 4H), 1.44-1.27 (m, 6H); ¹⁹F NMR (282MHz, DMSO) δ −60.74; MS(ES+) 562.5 (M+1); (ES−) 596.3 (M+Cl); Analysiscalculated for C₃₂H₃₄F₃N₅O.H₂O: C, 66.31; H, 6.26; N, 12.08; Found: C,66.47; H, 6.26; N, 11.76.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((pentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(172b) Step-1: Preparation of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(pentylamino-phenyl-methyl)-phenyl]-amide (172a)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(hydroxy-phenyl-methyl)-phenyl]-amide (144a) (1.0 g, 2.162 mmol) indichloromethane (50 mL) at 0° C. was added thionyl chloride (0.514 g,4.325 mmol) and stirred at room temperature for 3 h. Amyl amine (0.941g, 10.81 mmol) was added and stirred for 30 min. The reaction mixturewas concentrated in vacuum to dryness. The residue obtained wasdissolved in acetonitrile (20 mL) and added Amyl amine (0.941 g, 10.81mmol). The reaction mixture was heated at reflux overnight, cooled toroom temperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(pentylamino-phenyl-methyl)-phenyl]-amide (172a) (1.050 gm) as Yellowpowder; MS (ES) 530.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((pentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(172b)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid[3-(pentylamino-phenyl-methyl)-phenyl]-amide (172a) (1.0 g, 1.882 mmol)in MeOH (20 mL) cooled with ice/water was added nickel(II) chloridehexahydrate (0.53 g, 2.258 mmol) and followed by portion-wise additionof Sodium Borohydride (0.42 g, 11.292 mmol) over a period of 5 min. Thereaction mixture was stirred at room temperature for 2 hrs and quenchedwith N₁-(2-aminoethyl)ethane-1,2-diamine (0.48 g, 4.705 mmol) followedby stirring for additional 0.5 h. The reaction mixture was concentratedin vacuum to dryness, and the residue obtained was purified by flashcolumn chromatography two times (silica gel 66 g, eluting with 0-12%MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((pentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(172b) (0.020 gm) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68(s, 1H), 7.63 (s, 1H), 7.59 (s, 4H), 7.55-7.42 (m, 2H), 7.45-7.32 (m,3H), 7.32-7.23 (m, 2H), 7.25-7.13 (m, 2H), 4.73 (s, 1H), 3.92 (s, 1H),2.39 (t, J=7.2 Hz, 2H), 1.43 (d, J=7.7 Hz, 2H), 1.22 (q, J=3.5 Hz, 4H),0.90-0.77 (m, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −60.75; MS(ES+) 536.4(M+1); (ES−) 534.4 (M−1), 570.4 (M+Cl); Analysis calculated forC₃₀H₃₂F₃N₅O.1.25H₂O: C, 64.04; H, 6.27; N, 12.45; Found: C, 64.08; H,6.13; N, 11.73.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(173b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(173a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 2-methyl ethanolamine (0.812 g, 10.81 mmol) wasadded and stirred for 30 min. Then reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 2-methyl ethanolamine (0.812 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(173a) (0.88 gm) as off-white sticky liquid; MS (ES−) 518.3.

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(173b)

To a solution of2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(2-hydroxy-1-methyl-ethylamino)-phenyl-methyl]-phenyl}-amide (0.8 g,1.539 mmol) in MeOH (20 mL) cooled with ice/water was added nickel(II)chloride hexahydrate (0.491 g, 2.068 mmol) and followed by portion-wiseaddition of Sodium Borohydride (0.349 g, 9.234 mmol) over a period of 5min. The reaction mixture was stirred at room temperature for 2 hrs andquenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.635 g, 6.156 mmol)followed by stirring for additional 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness, and the residue obtained was purifiedby flash column chromatography two times (silica gel 70 g, eluting with0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(173b) (0.180 gm) as a Light yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.70 (s, 1H), 7.67 (s, 1H), 7.61 (d, J=2.1 Hz, 2H), 7.56-7.44 (m,3H), 7.40 (ddd, J=7.9, 3.6, 1.7 Hz, 3H), 7.34-7.14 (m, 5H), 5.64 (s,2H), 4.36 (s, 1H), 3.94 (s, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.37 (dd,J=7.9, 5.7 Hz, 2H), 2.11 (s, 3H)¹⁹F NMR (282 MHz, DMSO) δ −60.76;MS(ES+) 524.4 (M+1); (ES−) 558.3 (M+Cl); Analysis calculated forC₂₈H₂₈F₃N₅₀₂₂H₂O: C, 60.10; H, 5.76; N, 12.52; Found: C, 60.07; H, 5.70;N, 12.03.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 2-amino-2-methyl-1-propanol (0.964 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 2-amino-2-methyl-1-propanol (0.964 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174a) (0.9 gm) as yellow sticky semi-solid; MS (ES−) 532.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174b)

To a solution of1-(3-cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174a) (0.9 g, 1.68 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.479 g, 2.016 mmol) and followedby portion-wise addition of sodium borohydride (0.38 g, 10.08 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.46 g,4.5 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 65 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(174b) (0.100 gm) as a white crystal; ¹H NMR (300 MHz, DMSO-d₆) δ 10.66(s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.52-7.47 (m, 1H),7.46-7.42 (m, 2H), 7.42-7.27 (m, 4H), 7.27-7.19 (m, 3H), 7.19-7.11 (m,1H), 4.97 (s, 1H), 4.64 (s, 1H), 3.20 (s, 2H), 0.86 (s, 6H); ¹⁹F NMR(282 MHz, DMSO) δ −60.73; MS(ES+) 538.4 (M+1); (ES−) 536.4 (M−1), 572.3(M+Cl); Analysis calculated for C₂₉H₃₀F₃N₅O₂.0.75H₂O: C, 63.20; H, 5.76;N, 12.71; Found: C, 63.11; H, 5.79; N, 12.02.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and C-(Tetrahydro-furan-2-yl)-methylamine (1.093 g,10.81 mmol) was added and stirred for 30 min. Then reaction mixture wasconcentrated in vacuum to dryness. The residue obtained was dissolved inacetonitrile (20 mL) and added C-(Tetrahydro-furan-2-yl)-methylamine(1.093 g, 10.81 mmol). The reaction mixture was heated at refluxovernight, cooled to room temperature and concentrated in vacuum todryness. The residue was dissolved in dichloromethane (20 mL), washedwith water (2×25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting 0-25% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175a) (1.1 gm) as yellow-brown oil MS (ES−) 544.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175b)

To a solution of1-(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175a) (1.0 g, 1.833 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.544 g, 2.291 mmol) and followedby portion-wise addition of Sodium Borohydride (0.416 g, 10.998 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.756 g, 7.332 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 70 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(175b) (0.280 gm) as a Off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 7.73-7.07 (m, 14H), 4.79 (s, 1H), 3.91 (d, J=6.9 Hz, 3H),3.74-3.64 (m, 1H), 3.65-3.51 (m, 1H), 2.51-2.40 (m, 2H), 1.82 (ddt,J=33.3, 13.6, 6.8 Hz, 3H), 1.51 (dq, J=10.9, 7.1 Hz, 1H); ¹⁹F NMR (282MHz, DMSO) δ −60.75; MS(ES+) 550.4 (M+1); (ES−) 548.4 (M−1), 584.4(M+Cl); Analysis calculated for C₃₀H₃₀F₃N₅O₂.1.25H₂O: C, 62.98; H, 5.73;N, 12.24; Found: C, 62.85; H, 5.57; N, 12.03.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and isoamyl amine (0.94 g, 10.81 mmol) was added andstirred for 30 min. Then reaction mixture was concentrated in vacuum todryness. The residue obtained was dissolved in acetonitrile (20 mL) andadded isoamyl amine (0.94 gm, 10.81 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (20mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-25% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176a) (1.0 gm) as yellow oil; MS (ES−) 530.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176b)

To a solution of1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176a) (1.0 g, 1.882 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.53 g, 2.258 mmol) and followedby portion-wise addition of Sodium Borohydride (42 g, 11.292 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.48 g,4.705 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 70 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(176b) (0.350 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68(s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (d, J=2.6 Hz, 2H), 7.52 (dt,J=7.8, 1.7 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.37(ddt, J=5.0, 3.9, 1.9 Hz, 3H), 7.31-7.12 (m, 5H), 4.73 (s, 1H), 3.89 (s,2H), 2.45-2.35 (m, 2H), 1.60 (dq, J=13.2, 6.6 Hz, 1H), 1.40-1.28 (m,2H), 0.80 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO) δ −60.73; MS(ES+)536.4 (M+1); (ES−) 570.4 (M+Cl); Analysis calculated forC₃₀H₃₂F₃N₅O.1.25H₂O: C, 64.56; H, 6.23; N, 12.55; Found: C, 64.42; H,6.00; N, 12.53.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 2-Methyl-butylamine (0.942 g, 10.81 mmol) wasadded and stirred for 30 min. Then reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 2-Methyl-butylamine (0.942 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177a) (0.8 gm) as yellow oil; MS (ES−) 530.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177b)

To a solution of afford1-(3-cyanophenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177a) (0.8 g, 1.505 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.43 g, 1.806 mmol) and followedby portion-wise addition of Sodium Borohydride (0.34 g, 9.03 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.388g, 3.762 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(177b) pure (0.400 gm) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 7.67-7.11 (m, 14H), 4.71 (s, 1H), 3.88 (s, 2H), 2.39-2.14(m, 2H), 1.57-1.32 (m, 2H), 1.07 (dt, J=13.8, 7.3 Hz, 1H), 0.92-0.71 (m,6H); ¹⁹F NMR (282 MHz, DMSO) δ −60.35; MS(ES+) 536.4 (M+1); (ES−) 570.3(M+Cl); Analysis calculated for C₃₀H₃₂F₃N₅O.0.75H₂O: C, 65.62; H, 6.15;N, 12.75; Found: C, 65.62; H, 6.25; N, 12.03.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178b) Step-1: Preparation ofN-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178a)

To a solution of (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL)at 0° C. was added thionyl chloride (0.514 g, 4.325 mmol) and stirred atroom temperature for 3 h. Check TLC and 2-(2-Hydroxy-ethylamino)-ethanol(1.13 g, 10.81 mmol) was added and stirred for 30 min. Then reactionmixture was concentrated in vacuum to dryness. The residue obtained wasdissolved in acetonitrile (20 mL) and added2-(2-Hydroxy-ethylamino)-ethanol (1.13 g, 10.81 mmol). The reactionmixture was heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (20 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-25% ethyl acetate inhexane) to affordN-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178a) (0.500 gm) as yellow oil. (MS) (ES−) 548.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178b)

To a solution ofN-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178a) (0.5 g, 0.910 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.25 g, 1.092 mmol) and followedby portion-wise addition of Sodium Borohydride (0.20 g, 5.46 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.23 g,2.275 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(178b) (0.080 gm) as a white crystal; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69(s, 1H), 7.74-7.33 (m, 10H), 7.36-7.22 (m, 2H), 7.27-7.14 (m, 2H), 4.84(s, 1H), 3.97 (s, 2H), 3.44 (t, J=6.9 Hz, 4H), 2.55 (t, J=6.9 Hz, 4H);¹⁹F NMR (282 MHz, DMSO) δ −60.57; MS (ES+) 554.4 (M+1); (ES−) 552.3(M−1), 588.3 (M+Cl); Analysis calculated for C₂₉H₃₀F₃N₅O₃.HCl.3H₂O: C,54.08; H, 5.79; N, 10.87; Found: C, 54.03; H, 5.78; N, 11.01.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and C-Pyridin-3-yl-methylamine (1.168 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added C-Pyridin-3-yl-methylamine (1.168 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179a) (0.580 gm) as a white solid; MS (ES−) 551.2 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179b)

To a solution of1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179a) (0.5 g, 0.9048 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.25 g, 1.085 mmol) and followedby portion-wise addition of Sodium Borohydride (0.26 g, 5.428 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.23 g,2.262 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(179b) (0.055 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68(s, 1H), 8.48 (s, 1H), 8.44 (d, J=4.9 Hz, 1H), 7.78-7.71 (m, 1H), 7.68(s, 1H), 7.62-7.57 (m, 2H), 7.58-7.51 (m, 1H), 7.48 (d, J=6.5 Hz, 2H),7.41 (d, J=6.1 Hz, 3H), 7.36-7.26 (m, 3H), 7.28-7.16 (m, 3H), 4.74 (s,1H), 3.93 (s, 2H), 3.62 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.43; MS(ES+) 557.4 (M+1); (ES−) 555.4 (M−1), 591.3 (M+Cl); Analysis calculatedfor C₃₁H₂₇F₃N₆O.HCl.3.25H₂O: C, 57.14; H, 5.34; N, 12.90; Found: C,57.37; H, 5.14; N, 12.33.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180b) Step-1: Preparation ofN-(3-((butylamino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and Butylamine (0.79 g, 10.81 mmol) was added andstirred for 30 min. Then reaction mixture was concentrated in vacuum todryness. The residue obtained was dissolved in acetonitrile (20 mL) andadded Butylamine (0.79 g, 10.81 mmol). The reaction mixture was heatedat reflux overnight, cooled to room temperature and concentrated invacuum to dryness. The residue was dissolved in dichloromethane (20 mL),washed with water (2×25 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (silicagel 40 g, eluting 0-25% ethyl acetate in hexane) to affordN-(3-((butylamino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180a) (0.960 gm) as a brown oil; MS (ES−) 516.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180b)

To a solution ofN-(3-((butylamino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180a) (0.960 g, 1.856 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.551 g, 2.32 mmol) and followedby portion-wise addition of Sodium Borohydride (0.421 g, 11.136 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.478 g, 4.527 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(180b) (0.040 gm) as a off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.76 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.66 (d, J=2.7 Hz, 2H), 7.63-7.45(m, 4H), 7.39 (d, J=7.1 Hz, 2H), 7.34-7.12 (m, 5H), 4.76 (s, 1H), 4.09(s, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.43 (q, J=7.3 Hz, 2H), 1.28 (q, J=7.3Hz, 2H), 0.83 (t, J=7.2 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −60.77; MS(ES+) 522.4 (M+1); (ES−) 520.3 (M−1), 556.4 (M+Cl); Analysis calculatedfor C₂₉H₃₀F₃N₅O.HCl.1.25H₂O: C, 60.00; H, 5.82; N, 12.06; Found: C,60.34; H, 5.95; N, 11.52.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 4-Amino-cyclohexanol (1.25 g, 10.81 mmol) wasadded and stirred for 30 min. Then reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added trans-4-Amino-cyclohexanol (1.25 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181a) (0.600 gm) as a brownish solid; MS (ES−) 558.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181b)

To a solution of1-(3-cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181a) (0.600 g, 1.072 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.3 g, 2.32 mmol) and followed byportion-wise addition of Sodium Borohydride (0.2g, 6.432 mmol) over aperiod of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.276g, 2.68 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(181b) pure (0.140 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 7.58-7.47 (m, 3H), 7.39-7.29(m, 3H), 7.48-7.30 (m, 4H), 7.31-7.22 (m, 2H), 7.24-7.06 (m, 3H), 4.93(s, 1H), 4.43 (s, 1H), 3.82 (s, 2H), 2.31-2.11 (m, 1H), 1.94-1.83 (m,1H), 1.79-1.66 (m, 2H), 1.18-0.86 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ−60.73; MS (ES+) 564.4 (M+1); (ES−) 562.5 (M−1), 598.4 (M+Cl); Analysiscalculated for C₃₁H₃₂F₃N₅O₂.2.25H₂O: C, 61.63; H, 6.09; N, 11.59; Found:C, 61.69; H, 5.89; N, 11.38.

Step-1: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(182a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 1-Amino-propan-2-ol (0.811 g, 10.81 mmol) wasadded and stirred for 30 min. Then reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 1-Amino-propan-2-ol (0.811 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(182a) (0.600 gm) as a brownish oil; MS (ES−) 518.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(182b)

To a solution of afford1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(182a) (0.600 g, 1.154 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.32 g, 1.38 mmol) and followedby portion-wise addition of Sodium Borohydride (0.26 g, 6.924 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.29 g,2.885 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(182b) pure (0.020 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (d, J=1.8 Hz, 1H), 7.64 (s, 1H), 7.61-7.34 (m, 8H), 7.33-7.15 (m,5H), 4.75 (s, 1H), 4.68-4.40 (m, 1H), 3.89 (s, 2H), 3.73 (q, J=6.7, 6.3Hz, 1H), 2.35 (d, J=6.0 Hz, 2H), 1.02 (d, J=6.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO) δ −60.74; MS (ES+) 524.4 (M+1); (ES−) 522.3 (M−1), 558.3(M+Cl); Analysis calculated for C₂₈H₂₈F₃N₅O₂.2.75H₂O: C, 58.68; H, 5.89;N, 12.22; Found: C, 59.01; H, 5.60; N, 11.89.

Preparation ofN-(3-(((3-(1H-Imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183b) Step-1: Preparation ofN-(3-(((3-(1H-imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 3-Imidazol-1-yl-propylamine (1.35 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 3-Imidazol-1-yl-propylamine (1.35 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to affordN-(3-(((3-(1H-imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183a) (0.350 gm) as a brownish oil; MS (ES−) 568.3 (M−1).

Step-2: Preparation ofN-(3-(((3-(1H-Imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183b)

To a solution ofN-(3-(((3-(1H-imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183a) (0.350 g, 0.6144 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel (II) chloride hexahydrate (0.17 g, 0.737 mmol) and followedby portion-wise addition of Sodium Borohydride (0.139 g, 3.686 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.15 g, 1.536 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnishN-(3-(((3-(1H-Imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(183b) (0.050 gm) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.71(s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.55-7.35 (m, 8H), 7.33-7.24 (m,3H), 7.19 (q, J=7.0, 6.5 Hz, 2H), 7.10 (t, J=1.1 Hz, 1H), 6.83 (t, J=1.1Hz, 1H), 5.90 (s, 2H), 4.71 (s, 1H), 4.02 (t, J=7.0 Hz, 2H), 3.96 (s,2H), 2.37-2.34 (m, 2H), 1.88 (q, J=6.5 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO)δ −60.76; MS (ES+) 574.4 (M+1); (ES−) 572.4 (M−1), 608.3 (M+Cl);Analysis calculated for C₃₁H₃₀F₃N₇O.HCl.0.75H₂O: C, 59.71; H, 5.25; N,15.72; Found: C, 60.09; H, 5.43; N, 15.48.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and N,N,N′-Trimethyl-ethane-1,2-diamine (1.104 g,10.81 mmol) was added and stirred for 30 min. Then reaction mixture wasconcentrated in vacuum to dryness. The residue obtained was dissolved inacetonitrile (20 mL) and added N,N,N′-Trimethyl-ethane-1,2-diamine(1.104 g, 10.81 mmol). The reaction mixture was heated at refluxovernight, cooled to room temperature and concentrated in vacuum todryness. The residue was dissolved in dichloromethane (20 mL), washedwith water (2×25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting 0-25% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184a) (0.200 gm) as a brownish oil; MS (ES−) 488.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184b)

To a solution of1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184a) (0.190 g, 0.347 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.103 g, 0.433 mmol) and followedby portion-wise addition of Sodium Borohydride (0.078 g, 2.082 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.089 g, 0.867 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(184b) (0.025 gm) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 7.72 (s, 1H), 7.66-7.09 (m, 13H), 4.06 (s, 1H), 3.86 (s,2H), 2.10 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ −60.75; MS (ES+) 494.3(M+1); (ES−) 492.3 (M−1), 528.3 (M+Cl); Analysis calculated forC₂₇H₂₆F₃N₅O.1.5H₂O: C, 62.30; H, 5.62; N, 13.45; Found: C, 62.27; H,6.18; N, 11.54.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and Cyclohexylamine (1.07 g, 10.81 mmol) was addedand stirred for 30 min. Then reaction mixture was concentrated in vacuumto dryness. The residue obtained was dissolved in acetonitrile (20 mL)and added Cyclohexylamine (1.07 g, 10.81 mmol). The reaction mixture washeated at reflux overnight, cooled to room temperature and concentratedin vacuum to dryness. The residue was dissolved in dichloromethane (20mL), washed with water (2×25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting 0-25% ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185a) (0.9 gm) as yellow-brown sticky liquid; MS (ES−) 542.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185b)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185a) (0.9 g, 1.655 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.491 g, 2.069 mmol) and followedby portion-wise addition of Sodium Borohydride (0.375 g, 9.93 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.682g, 6.62 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 70 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(185b) (0.160 gm) as a Off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H), 7.65-7.57 (m, 3H), 7.57-7.42 (m, 3H), 7.42-7.12 (m, 8H),4.97 (s, 1H), 3.91 (s, 2H), 2.20 (d, J=11.9 Hz, 1H), 1.89 (d, J=8.1 Hz,2H), 1.63 (s, 2H), 1.49 (s, 1H), 1.16-0.97 (m, 5H); ¹⁹F NMR (282 MHz,DMSO) δ −60.76; MS (ES+) 548.4 (M+1); (ES−) 546.4 (M−1), 582.3 (M+Cl);Analysis calculated for C₃₁H₃₂F₃N₅O.1.5H₂O: C, 64.79; H, 6.14; N, 12.19;Found: C, 64.97; H, 5.85; N, 11.81.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and Pyridin-4-yl-methylamine (1.168 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added C-Pyridin-4-yl-methylamine (1.168 g, 10.805 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186a) (0.3 gm) as red oil; MS (ES−) 551.2 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186b)

To a solution of1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186a) (0.3 g, 0.543 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.170 g, 0.716 mmol) and followedby portion-wise addition of Sodium Borohydride (0.123 g, 3.258 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.140 g, 1.357 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 70 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(186b) (0.065 gm) as a off white Solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 8.56-8.43 (m, 1H), 7.73-7.15 (m, 17H), 4.73 (s, 1H), 3.93(s, 2H), 3.62 (d, J=5.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.51; MS(ES+) 557.4 (M+1); (ES−) 555.4 (M−1), 591.3 (M+Cl); Analysis calculatedfor C₃₁H₂₇F₃N₆O.2.25H₂O: C, 62.36; H, 5.32; N, 14.07; Found: C, 62.58;H, 5.30; N, 13.36.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 1,1-Dimethyl-propylamine (0.942 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 1,1-Dimethyl-propylamine (0.942 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187a) (0.480 gm) as yellow sticky oil; MS (ES−) 530.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187b)

To a solution of1-(3-cyanophenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187a) (0.480 g, 0.910 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.268 g, 1.128 mmol) and followedby portion-wise addition of Sodium Borohydride (0.204 g, 5.41 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.372g, 3.612 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 60 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(187b) pure (0.080 gm) as a white crystal; ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 7.70-7.07 (m, 14H), 4.94 (s, 1H), 4.04 (s, 2H), 0.90 (s,9H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79; MS (ES+) 536.3 (M+1); (ES−) 534.3(M−1), 570.1 (M+Cl).

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and Cyclobutylamine (0.768 g, 10.81 mmol) was addedand stirred for 30 min. Then reaction mixture was concentrated in vacuumto dryness. The residue obtained was dissolved in acetonitrile (20 mL)and added Cyclobutylamine (0.768 g, 10.805 mmol). The reaction mixturewas heated at reflux overnight, cooled to room temperature andconcentrated in vacuum to dryness. The residue was dissolved indichloromethane (20 mL), washed with water (2×25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting 0-25% ethyl acetate inhexane) to afford1-(3-cyanophenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188a) (0.7 gm) as red oil; MS (ES−) 514.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188b)

To a solution of1-(3-cyanophenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188a) (0.7 g, 1.032 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.29 g, 1.23 mmol) and followedby portion-wise addition of Sodium Borohydride (0.23 g, 6.192 mmol) overa period of 5 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.266g, 2.58 mmol) followed by stirring for additional 0.5 h. The reactionmixture was concentrated in vacuum to dryness, and the residue obtainedwas purified by flash column chromatography (silica gel 70 g, elutingwith 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(188b) (0.120 gm) as a Light Yellow Solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.56-7.50 (m, 2H),7.51-7.12 (m, 10H), 4.72 (s, 1H), 3.82 (s, 2H), 3.07-2.89 (m, 1H), 1.99(dt, J=13.1, 7.4 Hz, 2H), 1.74 (dp, J=18.1, 9.3, 8.8 Hz, 2H), 1.60-1.35(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.75; MS (ES+) 520.3 (M+1); (ES−)518.3 (M−1), 554.2 (M+Cl): Analysis calculated for C₂₈H₂₈F₃N₅O.H₂O: C,64.79; H, 5.62; N, 13.03; Found: C, 64.99; H, 5.58; N, 12.95.

Preparation ofN-(3-(((4-Aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(189b) Step-1: Preparation ofN-(3-(((4-aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(189a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 4-Aminomethyl-phenylamine (1.31 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 4-Aminomethyl-phenylamine (1.31 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to affordN-(3-(((4-aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(189a) (0.5 gm) as yellow oil; MS (ES−) 565.3 (M−1).

Step-2: Preparation ofN-(3-(((4-Aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(189b)

To a solution of 2 afford2-(3-Cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(4-amino-benzylamino)-phenyl-methyl]-phenyl}-amide (0.5 g, 0.884mmol) in MeOH (20 mL) cooled with ice/water was added nickel(II)chloride hexahydrate (0.26 g, 1.105 mmol) and followed by portion-wiseaddition of Sodium Borohydride (0.200 g, 5.304 mmol) over a period of 5min. The reaction mixture was stirred at room temperature for 2 hrs andquenched with N¹-(2-aminoethyl)ethane-1,2-diamine (0.364 g, 3.536 mmol)followed by stirring for additional 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness, and the residue obtained was purifiedby flash column chromatography (silica gel 60 g, eluting with 0-12%MeOH/DCM) to furnish-(3-Aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid{3-[(4-amino-benzylamino)-phenyl-methyl]-phenyl}-amide pure (0.020 gm)as a white Solid and mix (0.060 gm) as a off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.34 (s, 3H), 7.77-7.68 (m, 2H), 7.66 (s,1H), 7.62-7.17 (m, 11H), 6.96 (d, J=8.1 Hz, 2H), 6.57-6.43 (m, 2H), 5.05(s, 3H), 4.12 (s, 2H), 3.67-3.43 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.80; MS (ES+) 571.3 (M+1); (ES−) 569.3 (M−1), 605.3 (M+Cl); Analysiscalculated for C₃₂H₂₉F₃N₆O.HCl.1.5H₂O: C, 60.61; H, 5.25; N, 13.25;Found: C, 60.56; H, 5.20; N, 13.31.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 2-Methylsulfanyl-ethylamine (0.985 g, 10.81 mmol)was added and stirred for 30 min. Then reaction mixture was concentratedin vacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 2-Methylsulfanyl-ethylamine (0.985 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190a) (0.81 gm) as Light brown oil; MS (ES−) 534.3 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190b)

To a solution of1-(3-cyanophenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190a) (0.8 g, 1.493 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.443 g, 1.866 mmol) and followedby portion-wise addition of Sodium Borohydride (0.338 g, 8.958 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN¹-(2-aminoethyl)ethane-1,2-diamine (0.616 g, 5.972 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(190b) (0.075 gm) as a Light yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.72 (s, 1H), 7.75-7.13 (m, 14H), 6.04 (s, 2H), 4.81 (s, 1H), 3.97(s, 2H), 2.60 (s, 4H), 1.98 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −60.77;MS (ES+) 540.3 (M+1); (ES−) 538.2 (M−1), 601.3 (M+Cl); Analysiscalculated for C₂₈H₂₈F₃N₅OS.0.5H₂O: C, 61.30; H, 5.33; N, 12.77; Found:C, 61.20; H, 5.27; N, 12.01.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191b) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191a)

To a solution of1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(144a) (1.0 g, 2.162 mmol) in dichloromethane (50 mL) at 0° C. was addedthionyl chloride (0.514 g, 4.325 mmol) and stirred at room temperaturefor 3 h. Check TLC and 3-Amino-propan-1-ol (0.811 g, 10.81 mmol) wasadded and stirred for 30 min. Then reaction mixture was concentrated invacuum to dryness. The residue obtained was dissolved in acetonitrile(20 mL) and added 3-Amino-propan-1-ol (0.811 g, 10.81 mmol). Thereaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane (20 mL), washed with water (2×25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel 40 g, eluting 0-25%ethyl acetate in hexane) to afford1-(3-cyanophenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191a) (0.65 gm) as Brown syrup; MS (ES−) 518.3 (M−1).

Step-2: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191b)

To a solution of1-(3-cyanophenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191a) (0.6 g, 1.154 mmol) in MeOH (20 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (0.343 g, 1.443 mmol) and followedby portion-wise addition of sodium borohydride (0.261 g, 6.924 mmol)over a period of 5 min. The reaction mixture was stirred at roomtemperature for 2 hrs and quenched withN-(2-aminoethyl)ethane-1,2-diamine (0.476 g, 4.616 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness, and the residue obtained was purified by flash columnchromatography (silica gel 60 g, eluting with 0-12% MeOH/DCM) to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(191b) (0.060 gm) as a light yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.73 (s, 1H), 7.69 (s, 1H), 7.64 (d, J=2.8 Hz, 2H), 7.60-7.45 (m,4H), 7.40 (d, J=1.7 Hz, 1H), 7.37 (s, 1H), 7.33-7.24 (m, 3H), 7.20 (dt,J=8.9, 5.6 Hz, 2H), 4.74 (s, 1H), 4.09 (s, 2H), 3.43 (m, 2H), 2.46 (m,2H), 1.60 (p, J=6.8 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80, MS (ES+)524.3 (M+1); (ES−) 558.2 (M+Cl); Analysis calculated forC₂₈H₂₈F₃N₅O₂.HCl.1.5H₂O: C, 57.29; H, 5.49; N, 11.93; Found: C, 57.37;H, 5.35; N, 12.31.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(benzo[d][1,3]dioxol-4-yl(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(192f)

Compound (192f) was prepared starting frombenzo[d][1,3]dioxole-4-carbaldehyde (192a) (10 mmol) in five steps asshown in scheme 192 using procedure as reported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(benzo[d] [1,3]dioxol-4-yl(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(192f) (30 mg) as an off white solid; ¹H NMR (300 MHz, Methanol-d₄) δ7.66 (t, J=1.9 Hz, 1H), 7.61-7.55 (m, 1H), 7.53-7.41 (m, 4H), 7.35 (s,1H), 7.30-7.17 (m, 2H), 6.84 (dd, J=8.0, 1.4 Hz, 1H), 6.75 (t, J=7.8 Hz,1H), 6.67 (dd, J=7.6, 1.4 Hz, 1H), 5.87 (s, 2H), 4.99 (s, 1H), 4.04 (s,2H), 2.44-2.28 (m, 2H), 1.01-0.83 (m, 1H), 0.50-0.38 (m, 2H), 0.10-−0.01(m, 2H); ¹⁹F NMR (282 MHz, MeOD) δ −63.76; MS (ES+) 564.3 (M+1); (ES−)598.3 (M+Cl); Analysis calculated for C₃₀H₂₈F₃N₅O₃.HCl 1.75H₂O: C,57.05; H, 5.19; N, 11.09; Found: C, 57.31; H, 5.25; N, 10.74.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(o-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(193f)

Compound (193f) was prepared starting from 2-methylbenzaldehyde (193a)(10 mmol) in five steps as shown in scheme 193 using procedure asreported in scheme-109 to furnish1-(3-(Aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(o-tolyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(193f) (30 mgs) as a light green solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.94 (s, 1H), 9.84 (s, 2H), 8.41 (s, 3H), 7.92-7.17 (m, 13H), 5.61 (s,1H), 4.22-4.03 (m, 2H), 2.83-2.67 (m, 2H), 2.31 (s, 3H), 1.19-1.01 (m,1H), 0.54 (d, J=8.2 Hz, 2H), 0.36-0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO)δ −60.80; MS (ES+) 534.3 (M+1); (ES−) 532.3 (M−1), 568.2 (M+Cl);Analysis calculated for C₃₀H₃₀F₃N₅O.2HCl.2.75H₂O: C, 54.92; H, 5.76; N,10.68; Found: C, 55.08; H, 5.54; N, 10.50.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(194f)

Compound (194f) was prepared starting from 2-chlorobenzaldehyde (194a)(10 mmol) in five steps as shown in scheme 194 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-((2-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(194f) (20 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s,1H), 7.77-7.65 (m, 1H), 7.64-7.49 (m, 4H), 7.49-7.10 (m, 8H), 5.24 (s,1H), 3.78 (s, 2H), 2.28 (dd, J=6.8, 2.6 Hz, 2H), 0.99-0.83 (m, 1H),0.49-0.30 (m, 2H), 0.11-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.72;MS (ES+) 554.3 (M+1); (ES−) 552.3 (M−1); Analysis calculated forC₂₉H₂₇ClF₃N₅O.0.5H₂O: C, 61.87; H, 5.01; N, 12.44; Found: C, 61.68; H,5.01; N, 12.43.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(3-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(195f)

Compound (195f) was prepared starting from 3-fluorobenzaldehyde (195a)(10 mmol) in five steps as shown in scheme 195 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(3-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(195f) (40 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.11 (s, 2H), 8.39 (s, 3H), 7.88 (s, 1H), 7.73 (s, 1H), 7.68 (s,1H), 7.67-7.39 (m, 9H), 7.23 (dt, J=8.0, 4.8 Hz, 1H), 5.65 (d, J=7.0 Hz,1H), 4.13 (d, J=5.7 Hz, 2H), 2.79-2.65 (m, 2H), 1.26-1.05 (m, 1H),0.65-0.48 (m, 2H), 0.44-0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80,−111.69; MS (ES+) 538.4 (M+1); (ES−) 572.3 (M+Cl); Analysis calculatedfor C₂₉H₂₇F₄N₅O.2HCl.3.5H₂O: C, 51.71; H, 5.39; N, 10.40; Found: C,51.94; H, 5.24; N, 10.33.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(196f)

Compound (196f) was prepared starting from 2,4-difluorobenzaldehyde(196a) (10 mmol) in five steps as shown in scheme 196 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(196f) (40 mgs) as a pale orange solid. H NMR (300 MHz, DMSO-d₆) δ 10.95(s, 1H), 10.19 (s, 1H), 8.42 (s, 3H), 8.07 (d, J=13.3 Hz, 1H), 7.85-7.22(m, 11H), 5.72 (s, 1H), 4.13 (s, 2H), 2.87-2.65 (m, 2H), 1.21-1.00 (m,1H), 0.67-0.40 (m, 2H), 0.38-0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.80, −108.86, −111.97; MS (ES+) 556.3 (M+1); (ES−) 554.4 (M−1), 590.4(M+Cl); Analysis calculated for C₂₉H₂₆F₅N₅O.2HCl 1.5H₂O: C, 53.14; H,4.77; N, 10.68; Found: C, 53.05; H, 4.68; N, 11.21.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(197f)

Compound (197f) was prepared starting from 2,5-difluorobenzaldehyde(197a) (10 mmol) in five steps as shown in scheme 197 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(197f) (40 mgs) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s,1H), 8.35 (s, 3H), 7.72 (d, J=1.9 Hz, 1H), 7.71-7.41 (m, 6H), 7.42-7.07(m, 5H), 5.15 (s, 1H), 4.13 (s, 2H), 2.42-2.27 (m, 2H), 1.00-0.89 (m,1H), 0.41 (m, 2H), 0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80,−118.15, −124.26. MS (ES+) 556.3 (M+1); (ES−) 590.3 (M+Cl); Analysiscalculated for C₂₉H₂₆F₅N₅O.HCl.2H₂O: C, 55.46; H, 4.98; N, 11.15; Found:C, 55.18; H, 4.82; N, 11.39.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,6-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(198f)

Compound (198f) was prepared starting from 2,6-difluorobenzaldehyde(198a) (10 mmol) in five steps as shown in scheme 198 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,6-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(198f) (10 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.72 (s,1H), 7.65-7.49 (m, 4H), 7.47-7.40 (m, 3H), 7.42-7.23 (m, 3H), 7.09 (dd,J=19.0, 8.0 Hz, 2H), 5.24 (s, 1H), 3.77 (d, J=2.1 Hz, 2H), 2.48-2.22 (m,2H), 0.90 (dp, J=13.0, 6.1 Hz, 1H), 0.44-0.33 (m, 2H), 0.21-0.03 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.71, −114.27; MS (ES+) 556.4 (M+1);(ES−) 554.4 (M−1), 590.3 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((6-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(199f)

Compound (199f) was prepared starting from 4-chlorobenzaldehyde (199a)(10 mmol) in five steps as shown in scheme 199 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-((6-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(199f) (15 mgs) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s,1H), 7.63 (t, J=1.8 Hz, 1H), 7.59-7.49 (m, 3H), 7.44-7.14 (m, 9H), 4.82(s, 1H), 3.77 (s, 2H), 2.27 (d, J=6.6 Hz, 2H), 1.00-0.81 (m, 1H),0.49-0.28 (m, 2H), 0.12-−0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.72;MS (ES+) 556.3 (M+1); Analysis calculated for C₂₉H₂₇ClF₃N₅O: C, 62.87;H, 4.91; N, 12.64; Found: C, 62.63; H, 5.01; N, 12.55.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((2,4-dichlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(200f)

Compound (200f) was prepared starting from 2,4-dichlorobenzaldehyde(200a) (10 mmol) in five steps as shown in scheme 200 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-((2,4-dichlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(200f) (30 mgs) as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.72 (s,1H), 7.73 (d, J=8.4 Hz, 1H), 7.66-7.41 (m, 9H), 7.27 (t, J=7.7 Hz, 1H),7.15 (d, J=7.8 Hz, 1H), 6.67 (s, 2H), 5.20 (s, 1H), 4.01 (s, 2H), 2.27(dd, J=6.3, 3.4 Hz, 2H), 0.99-0.77 (m, 1H), 0.47-0.31 (m, 2H),0.10-−0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.78; MS (ES+) 588.3,590.3 (M+1); Analysis calculated for C₂₉H₂₆C₁₂F₃N₅O.1.5H₂O: C, 56.59; H,4.75; N, 11.38; Found: C, 56.67; H, 4.87; N, 10.99.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(201f)

Compound (201f) was prepared starting from 2,4-dimethylbenzaldehyde(201a) (10 mmol) in five steps as shown in scheme 201 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(201f) (110 mgs) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.91(s, 1H), 9.71 (s, 1H), 8.34 (s, 3H), 7.78-7.37 (m, 10H), 7.14 (d, J=7.8Hz, 1H), 7.05 (s, 1H), 5.59 (s, 1H), 4.13 (s, 2H), 2.85-2.67 (m, 2H),2.32-2.21 (m, 6H), 1.17-0.96 (m, 1H), 0.64-0.48 (m, 2H), 0.23 (d, J=19.7Hz, 2H). ¹⁹F NMR (282 MHz, DMSO) δ −60.80; MS (ES+) 548.4 (M+1); (ES−)582.3 (M+Cl); Analysis calculated for C₃₁H₃₂F₃N₅O.2HCl 3.25H₂O: C,54.83; H, 6.01; N, 10.31; Found: C, 54.90; H, 6.02; N, 9.64.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(202f)

Compound (202f) was prepared starting from 2,5-dimethylbenzaldehyde(202a) (10 mmol) in five steps as shown in scheme 202 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(202f) (60 mgs) as a light green solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 9.73 (s, 2H), 8.35 (d, J=14.1 Hz, 3H), 7.80 (s, 1H), 7.73(s, 1H), 7.69-7.42 (m, 8H), 7.15-7.05 (m, 2H), 5.59 (s, 1H), 4.12 (d,J=5.1 Hz, 2H), 2.96-2.63 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.21-1.01(m, 1H), 0.56 (d, J=8.0 Hz, 2H), 0.28 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.80; MS (ES+) 548.4 (M+1); Analysis calculated forC₃₁H₃₂F₃N₅O.4HCl.2H₂O: C, 49.81; H, 5.66; N, 9.37; Found: C, 49.85; H,5.53; N, 8.86.

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-((4-(tert-butyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(203f)

Compound (203f) was prepared starting from 4-(tert-butyl)benzaldehyde(203a) (10 mmol) in five steps as shown in scheme 203 using procedure asreported in scheme-109 to furnish1-(3-(aminomethyl)phenyl)-N-(3-((4-(tert-butyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(203f) (20 mgs) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 7.66 (s, 1H), 7.61 (s, 2H), 7.57-7.34 (m, 4H), 7.30 (s,4H), 7.24-7.18 (m, 2H), 4.77 (s, 1H), 3.95 (s, 2H), 2.27 (d, J=6.5 Hz,2H), 1.23 (s, 9H), 1.02-0.70 (m, 1H), 0.46-0.29 (m, 2H), 0.08-0.02 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.77; MS (ES+) 576.4 (M+1); Analysiscalculated for C₃₃H₃₆F₃N₅O.2H₂O: C, 64.80; H, 6.59; N, 11.45; Found: C,65.10; H, 6.38; N, 10.61.

Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(204d) and(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(204e)

Compounds 204d and 204e can be prepared as shown in scheme 205 fromcompound 58b.

Analytical data for(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(204d), free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.53(bs, 1H) 8.58 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.7, 1.6 Hz, 1H), 7.75 (dt,J=8.1, 2.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.50 (s, 1H), 7.47-7.36 (m, 2H),7.30 (m, 3H), 7.18 (t, J=9.4 Hz, 1H), 3.77 (s, 2H), 2.37-2.03 (m, 2H),1.03 (m, 2H), 0.63 (m, 1H), 0.41-0.24 (m, 2H), −0.08 (m, 2H); ¹⁹F NMR(282 MHz, DMSO) δ −60.74, −124.19; MS (ES+) 553.4 (M+1), (ES−) 551.4(M−1); Optical rotation: [α]_(D)=(−) 1.87 [CH₃OH, 0.535].

Analytical data for(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (204e), free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.57 (bs, 1H), 8.61 (m, 1H), 8.35 (m, 1H), 7.87-7.08 (m, 10H), 3.73 (s,2H), 2.38-2.05 (m, 2H), 1.07 (m, 2H), 0.65 (m, 1H), 0.36 (m, 2H), 0.00(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.43, −124.00; MS (ES+) 553.4(M+1); [α]_(D)=(+) 0.685 [CH₃OH, 1.75].

Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(205d) and(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(205e)

Compounds 205d and 205e can be prepared as shown in scheme 205. Chiralpurity was checked using Chiral HPLC: AD-H column 90/10/0.2(Hexane/ethanol/TEA) 0.8 mL/min UV 260 nM, 45 mins run time (Temp 40°C.). Rt=20.976 (peak-1 for 205d); Rt=26.044 (peak-2 for 205e).

Analytical data for(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(205d), White solid as hydrochloride salt; MP: 252.6° C.; ¹H NMR (300MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.08 (s, 3H), 8.69-8.62 (m, 1H), 8.53 (s,3H), 7.89 (td, J=7.8, 1.9 Hz, 1H), 7.78-7.69 (m, 2H), 7.64 (m, 2H), 7.55(d, J=7.9 Hz, 1H), 7.51 (dd, J=3.6, 1.7 Hz, 1H), 7.49-7.43 (m, 1H), 7.41(m, 1H), 7.38 (m, 1H), 7.36-7.27 (m, 1H), 4.11 (q, J=5.5 Hz, 2H),2.67-2.50 (m, 2H), 1.27-1.15 (m, 1H), 1.03-0.89 (m, 1H), 0.75-0.58 (m,1H), 0.37 (m, 2H), 0.04-−0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.82,−120.56; MS (ES+) 553.4 (M+1), (ES−) 551.6 (M−1); Chiral Purity >99.9%ee; HPLC purity 98.4034%; Optical rotation: [α]_(D)=(−) 19.234 [CH₃OH,1.175].

Analytical data for(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(205e), White solid as hydrochloride salt; MP 227.9° C.; ¹H NMR (300MHz, DMSO-d₆) δ 10.81 (s, 1H), 9.02 (s, 3H), 8.66 (m, 1H), 8.42 (s, 3H),7.89 (td, J=7.8, 1.8 Hz, 1H), 7.73 (m, 1H), 7.70 (m, 1H), 7.67-7.59 (m,2H), 7.56 (d, J=7.9 Hz, 1H), 7.51 (dd, J=3.9, 2.0 Hz, 1H), 7.44 (m, 1H),7.39 (m, 1H), 7.36 (m, 1H), 7.34-7.28 (m, 1H), 4.12 (d, J=5.9 Hz, 2H),2.57-2.40 (m, 2H), 1.21 (m, 1H), 0.96 (m, 1H), 0.66 (m, 1H), 0.42-0.32(m, 2H), −0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.82, −120.56; MS(ES+) 553.4 (M+1), (ES−) 587.2 (M+Cl); Chiral Purity >99.9% ee; HPLCpurity >99.9%; Optical rotation: [α]_(D)=(+) 19.43 [CH₃OH, 0.525].

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206d) Step-1: Preparation ofN-(3-((bis(cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206a)

Compound 206a can be prepared from compound 144a as reported in step-1of Scheme-168 using bis-cyclopropylmethyl-amine (preparation reported byBaruah, Anima et al. in Preparation of novel benzylamine derivatives asCETP inhibitors; WO 2006/073973).

Step-2: Preparation of(−)-N-(3-((bis(cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206b)

Compound 206b can be obtained by preparative Chiral HPLC separation ofcompound 206a prepared in step-1; ¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s,1H), 8.11 (s, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H),7.76-7.68 (m, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.41-7.14 (m, 7H), 4.92 (s,1H), 2.44 (d, J=3.9 Hz, 4H), 0.90 (t, J=7.5 Hz, 2H), 0.47-0.30 (m, 4H),−0.04-−0.14 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ −60.95, −123.40; IR 2237cm⁻¹ (for —CN); MS (ES+) 588.3 (M+1); Optical rotation: [α]_(D)=(−)18.97 [CH₃OH, 2.52]; Analysis calculated for C₃₃H₂₉F₄N₅O: C, 67.45; H,4.97; N, 11.92; Found: C, 67.32; H, 5.08; N, 11.75.

Step-3: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206d)

To a stirred solution of(−)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206b) (6.0 g, 10.21 mmol) in anhydrous methanol (100 mL), cooled to 0°C., was added nickel(II) chloride hexahydrate (0.607 g, 2.55 mmol),sodium borohydride (2.90 g, 77 mmol) was added to the reaction mixturein small portions over a 45 min period. The reaction mixture was stirredfor 30 min at 0° C. and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (2.206 mL, 20.42 mmol) stirred for30 mins and concentrated in vacuum to dryness. The residue obtained wasstirred in water overnight. The solid was dissolved by adding conc. HCl(25.00 mL, 300 mmol). Insoluble solid was removed by filtration. Thefiltrate was nuetralized with solid NaOH (12 g, 300 mmol) and furtherbasified to pH=12 using 3 N NaOH. The pink solution was extracted withchloroform (2×100 mL). The organic layer was combined, dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 80 g, eluting with 0-25% methanol inchloroform) to furnish(−)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidefree base (206d) (2.18 g, 3.68 mmol, 36.1% yield) as a white foam; ¹HNMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H), 7.70-7.62 (m, 1H), 7.57 (s, 1H),7.52 (s, 1H), 7.47-7.25 (m, 8H), 7.24-7.15 (m, 2H), 4.91 (s, 1H), 3.79(s, 2H), 2.45 (dd, J=6.2, 2.3 Hz, 4H), 0.90 (tq, J=11.4, 6.5, 5.7 Hz,2H), 0.50-0.26 (m, 4H), −0.03-−0.18 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ−60.74, −123.73; MS (ES+) 592.4 (M+1); (ES−) 590.4 (M−1); HPLC(Rt=5.047, 98.4644); Optical rotation: [α]_(D)=(−) 1.51 [CH₃OH, 1.565];Analysis calculated for C₃₃H₃₃F₄N₅O.0.5H₂O: C, 65.99; H, 5.71; N, 11.66;Found: C, 66.29; H, 5.75; N, 11.57. The above solid (1.68 g, 2.8 mmol)was dissolved in ethanol (5 mL) and added conc. HCl (1.17 mL, 14 mmol),water (5 mL), stirred for 30 mins and concentrated in vacuum to drynessto afford 1.7 gm(−)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(206d) HCl salt as a white solid; MP 199° C.; ¹H NMR (300 MHz, DMSO-d₆)δ 11.61 (s, 1H), 10.86 (s, 1H), 8.52 (d, J=7.1 Hz, 3H), 8.20 (dd, J=7.0,2.3 Hz, 1H), 8.08-7.92 (m, 3H), 7.76-7.69 (m, 2H), 7.67-7.51 (m, 3H),7.46-7.31 (m, 4H), 5.81 (d, J=9.8 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 3.08(dtt, J=17.1, 8.4, 4.5 Hz, 4H), 1.20 (ddt, J=12.6, 8.5, 5.0 Hz, 2H),0.58 (ddq, J=7.4, 3.3, 1.9 Hz, 4H), 0.36-0.04 (m, 4H); ¹⁹F NMR (282 MHz,DMSO) δ −60.81, −120.39; MS (ES+) 592.4 (M+1); (ES−) 626.4 (M+Cl);Optical rotation: [α]_(D)=(−) 11.11 [CH₃OH, 1.17]; Analysis calculatedfor C₃₃H₃₃F₄N₅O.2HCl 1.75H₂O: C, 56.94; H, 5.57; Cl, 10.19; N, 10.06;Found: C, 56.98; H, 5.47; Cl, 10.44; N, 9.99.

Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-bromo-4-hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207j) Step-1: (3-aminophenyl)(4-(benzyloxy)-3-bromophenyl)methanol(207b) and (3-aminophenyl)(4-(benzyloxy)phenyl)methanol (207c)

To a stirred solution of 4-(benzyloxy)-3-bromobenzaldehyde (207a) (3.2g, 10 mmol) in THF (5 mL) was added(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL,12.00 mmol) at 0° C. The reaction was stirred for 14 h at roomtemperature, quenched by adding 2 N HCl (12.50 mL) and stirred for 6 h.The reaction mixture was treated with 2 N NaOH (15 mL) and extractedwith ethyl acetate (2×50 mL). The organic layers were combined washedwith saturated aqueous NH₄Cl (50 mL), dried over anhydrous MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% ethylacetate in hexane) to furnish a mixture of(3-aminophenyl)(4-(benzyloxy)-3-bromophenyl)methanol (207b) and(3-aminophenyl)(4-(benzyloxy)phenyl)methanol (207c) (3.0 gm).

Step-2: Preparation ofN-(3-((4-(benzyloxy)-3-bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207e) andN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207d)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.1 mmol) in DMF (10 mL) was added a mixture of(3-aminophenyl)(4-(benzyloxy)-3-bromophenyl)methanol (207e) and(3-aminophenyl)(4-(benzyloxy)phenyl)methanol (207d) (1 mmol),N-ethyl-N-isopropylpropan-2-amine (6 eq) and bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrOP, 1.1 eq) at room temperature. Thereaction mixture was stirred at room temperature for 24 h under nitrogenatmosphere. The reaction was diluted with ethyl acetate washed withwater, brine, dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel,eluting with ethyl acetate in hexanes] to furnish a mixture ofN-(3-((4-(benzyloxy)-3-bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207e) andN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207d).

Step-3: Preparation ofN-(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207f) andN-(3-((4-(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207g)

To a solution of mixture ofN-(3-((4-(benzyloxy)-3-bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207e) andN-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207d) (1.0 mmol) in dichloromethane (10 mL) at 0° C. was added thionylchloride (3 mmol) and stirred at room temperature for 4 h. The reactionmixture was concentrated in vacuum to dryness. The residue obtained wasdissolved in acetonitrile (10 mL) and added cyclopropylmethanamine (10mmol). The reaction mixture was heated at reflux overnight, cooled toroom temperature and concentrated in vacuum to dryness. The residue wasdissolved in dichloromethane, washed with water, dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel, eluting with ethyl acetate in hexane)to afford mixture (0.77 g) ofN-(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207f) andN-(3-((4-(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207g).

Step-4: Preparation of tert-butyl((4-(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate(207h) and tert-butyl3-(5-((3-((4-(benzyloxy)-3-bromophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(207i)

To a solution of mixture ofN-(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207f) andN-(3-((4-(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207g) (0.77 g) in MeOH (10 mL) cooled with ice/water was addednickel(II) chloride hexahydrate (0.25 eq) and Boc anhydride (4 eq)followed by portionwise addition of sodium borohydride (6 eq) over aperiod of 15 min. The reaction mixture was stirred at room temperaturefor 2 hrs and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (2 eq)followed by stirring for additional 0.5 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was dissolvedin chloroform and water. The aqueous layer was separated extracted againwith chloroform. The combined extracts were washed with brine, driedover MgSO₄ filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel, eluting with Ethylacetate/hexane) to furnish:

-   -   1. tert-butyl        ((4-(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate        (207h) (0.24 g, 22%) as an off-white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.72 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.56 (s, 1H),        7.49-7.38 (m, 9H), 7.34 (d, J=7.2 Hz, 4H), 7.17 (q, J=8.6 Hz,        2H), 6.93 (d, J=7.9 Hz, 1H), 6.16 (s, 1H), 5.21 (s, 2H), 4.18        (d, J=6.2 Hz, 2H), 3.22-2.91 (m, 2H), 1.37 (s, 9H), 1.30-1.23        (m, 9H), 0.75-0.56 (m, 1H), 0.23 (d, J=8.2 Hz, 2H), −0.04-−0.14        (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.71; MS (ES+) 848.8.5        (M+Na); (ES−) 824.5 (M−1).    -   2. tert-butyl        3-(5-((3-((4-(benzyloxy)-3-bromophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate        (207i) (0.35 g, 39.6%) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 10.69 (s, 1H), 7.61 (d, J=2.0 Hz, 2H), 7.57 (s, 1H),        7.53 (s, 1H), 7.45-7.39 (m, 6H), 7.37-7.32 (m, 4H), 7.25 (t,        J=7.8 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H),        5.15 (s, 2H), 4.77 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 2.26 (d,        J=6.4 Hz, 2H), 1.35 (s, 9H), 0.94-0.84 (m, 1H), 0.46-0.28 (m,        2H), 0.05 (t, J=4.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79;        MS (ES+) 804.4, 806.3 (M+1).

Step-5: Preparation of1-(3-(Aminomethyl)phenyl)-N-(3-((3-bromo-4-hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207j)

To a solution of tert-butyl3-(5-(3-((4-(benzyloxy)-3-bromophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(207i) (0.120 g, 0.149 mmol) in dichloromethane (10 mL) cooled to 0° C.was added dropwise under a nitrogen atmosphere tribromoborane (1 Msolution in dichloromethane, 0.596 mL, 0.596 mmol). The reaction mixturewas allowed to warm to room temperature and stirred at room temperature2 h. The reaction mixture was quenched with methanol (5 mL) andconcentrated in vacuum to dryness. The residue obtained was trituratedwith methanol and dried under vacuum, this step was repeated four timesto furnish crude product. The residue obtained was purified twice byflash column chromatography [silica gel 12 g and 4 g, eluting withCMA-80 in chloroform from 0-100%] to furnish1-(3-(aminomethyl)phenyl)-N-(3-((3-bromo-4-hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(207j) (0.045 g, 0.073 mmol, 49.1% yield) as a brownish orange solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 10.62 (s, 1H), 9.58 (s, 2H),8.26 (s, 3H), 7.81 (s, 1H), 7.76-7.71 (m, 2H), 7.67 (s, 1H), 7.62-7.46(m, 6H), 7.38 (dd, J=8.5, 2.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 5.56 (d,J=6.4 Hz, 1H), 4.24-4.06 (m, 2H), 2.72 (d, J=6.3 Hz, 2H), 1.08 (ddt,J=12.7, 8.3, 4.1 Hz, 1H), 0.56 (dt, J=9.4, 3.0 Hz, 2H), 0.30 (t, J=4.9Hz, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80; MS (ES+) 616.3 (M+2); (ES−)612.4 (M−2); HPLC purity (95.8256%); Analysis calculated forC₂₉H₂₇BrF₃N₅O₂.2.1HBr.2H₂O: C, 42.46; H, 4.07; Br, 30.19; N, 8.54;Found: C, 42.22; H, 3.99; Br, 30.56; N, 8.35.

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(208d) Step-1: Preparation of(+)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(208a)

To a stirred solution of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one(47c) (3.98 g, 22.69 mmol) in tetrahydrofuran (30 mL) was added(S)-2-methylpropane-2-sulfinamide (2.5 g, 20.63 mmol),tetraisopropoxytitanium (12.34 mL, 41.3 mmol) and heated at reflux for16 h. The reaction mixture was allowed to cool to room temperature,diluted with brine (20 mL) and tetrahydrofuran (100 mL). The solidseparated was removed by filtration and filtrate was concentrated invacuum. The residue was suspended in dichloromethane (300 mL), washedwith brine (50 mL) dried, filtered and concentrated in vacuum. The cruderesidue was purified by flash column chromatography (silica gel 40 g,eluting with ethyl acetate in hexanes) to afford(+)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(208a) (1.32 g, 4.74 mmol, 22.99% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.25 (d, J=2.3 Hz, 1H), 8.93 (dd, J=4.8, 1.7 Hz, 1H),8.46 (d, J=8.1 Hz, 1H), 7.75 (dd, J=8.0, 4.8 Hz, 1H), 3.69-3.41 (m, 2H),1.68 (q, J=7.4 Hz, 2H), 1.45 (s, 9H), 0.96 (m, 1H), 0.67-0.48 (m, 2H),0.30-0.22 (m, 2H); Optical Rotation [α]_(D)=(+) 25.77 [0.52, MeOH].

Step-2: Preparation of(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(208b)

To a stirred solution of(+)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(208a) (4.12 g, 14.80 mmol) in toluene (30 mL) at −20° C. was addeddropwise a freshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(29.6 mL, 29.6 mmol) over a period of 10 mins. The reaction mixture wasstirred at −20° C. for 1 h and quenched with 1N aqueous KHSO4 (25 mL).The reaction mixture was stirred for 1 h at room temperature andextracted with ethyl acetate (2×200 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL), dried andconcentrated in vacuum to dryness. The crude residue was purified byflash column chromatography (silica gel, 50 g eluting with ethyl acetatein hexanes 0 to 100%) to afford(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(208b) (1.15 g, 2.95 mmol, 19.95% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.51 (dd, J=2.5, 0.8 Hz, 1H), 8.40 (dd, J=4.7, 1.5 Hz,1H), 7.70 (dt, J=8.1, 2.0 Hz, 1H), 7.32 (ddd, J=8.1, 4.7, 0.8 Hz, 1H),6.90 (dd, J=11.3, 8.5 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.50 (ddd,J=8.5, 4.3, 2.4 Hz, 1H), 5.27 (s, 1H), 5.11 (s, 2H), 2.67-2.54 (m, 2H),1.12 (s, 10H), 0.90 (m, 1H), 0.65 (m, 1H), 0.41-0.29 (m, 2H),−0.01-−0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.66; MS (ES+)390.4 (M+1), 412.4 (M+Na), 779.6 (2M+1), 801.6 (2M+Na), (ES−) 388.3(M−1); Optical Rotation [α]_(D)=(+) 110.34 [0.145, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(208c)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (1.251 g, 3.25 mmol) in DMF (17 mL) was added(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(208b) (1.15 g, 2.95 mmol), N-ethyl-N-isopropylpropan-2-amine (2.57 mL,14.76 mmol) and bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop, 1.514 g, 3.25 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 6h, diluted with water (40 mL) and extracted with ethyl acetate (2×100mL). The organic layers were combined, washed with brine (50 mL), dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, elutingwith 0-100% ethyl acetate in hexanes) to furnish tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1)-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(208c) (1.2 g, 0.696 mmol, 53% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.55-8.45 (m, 1H), 8.41 (dd, J=4.7, 1.5 Hz,1H), 7.69 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.51 (t, J=6.3 Hz,1H), 7.42 (d, J=4.9 Hz, 2H), 7.38-7.30 (m, 3H), 7.25 (d, J=10.0 Hz, 2H),5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.73-2.54 (m, 2H), 1.38 (s, 9H),1.12 (s, 10H), 0.92 (m, 1H), 0.64 (m, 1H), 0.41-0.24 (m, 2H),−0.02-−0.19 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −123.10; MS(ES+) 757.4 (M+1), 779.4 (M+Na), (ES−) 755.4 (M−1) (+) 67.17 (0.265,methanol). Optical Rotation [α]_(D)=(+) 67.17 (0.265, methanol).

Step-4: Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(208d)

To a stirred solution of furnish tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(208c) (1 g, 1.321 mmol) in ethanol (20 mL) was added conc. HCl (1.101mL, 13.21 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was purifiedby flash column chromatography (silica gel, 24 g eluting with CMA 80 inchloroform 0 to 100%) to afford product which was repurified by flashcolumn chromatography (silica gel, 24 g eluting with methanol inchloroform 0 to 50%) to afford(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(208d) (560 mg, 1.013 mmol, 77% yield) free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.58 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.7, 1.6Hz, 1H), 7.75 (dt, J=8.1, 2.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.50 (s, 1H),7.47-7.36 (m, 2H), 7.30 (td, J=8.0, 7.4, 3.6 Hz, 3H), 7.18 (t, J=9.4 Hz,1H), 3.77 (s, 2H), 2.37-2.03 (m, 2H), 1.03 (t, J=6.4 Hz, 2H), 0.63 (td,J=9.0, 8.0, 4.3 Hz, 1H), 0.41-0.24 (m, 2H), −0.08 (td, J=5.3, 3.7 Hz,2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.73, −124.20; MS (ES+) 553.4 (M+1),(ES−) 551.4 (M−1).

To a stirred solution of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(208d) (495 mg, 0.896 mmol) free base in ethanol (5 mL) was added conc.HCl (0.373 mL, 4.48 mmol), water (3 mL) stirred for 10 mins andconcentrated to dryness to afford(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(208d) (0.491 g, 0.785 mmol, 88% yield, >99.99 ee) hydrochloride salt asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.60 (s, 3H),8.72-8.63 (m, 2H), 8.45 (s, 3H), 8.02 (d, J=8.4 Hz, 1H), 7.75-7.32 (m,9H), 4.11 (q, J=5.8 Hz, 2H), 2.64-2.54 (m, 2H), 1.10 (dd, J=17.8, 7.7Hz, 2H), 0.68 (d, J=8.0 Hz, 1H), 0.43-0.33 (m, 2H), 0.07-0.01 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −120.42 (d, J=10.5 Hz); MS (ES+)553.5 (M+1), (ES−) 551.5 (M−1); Optical Rotation [α]_(D)=(+) 2.55 [1.02,MeOH]; Chiral purity checked by performing chiral HPLC using chiral AD-Hcolumn, 1 mL/min, Solvent: 85% Hexane, 20% EtOH, 0.1% TEA, UV=260 nM,20° C. (>99.99 ee).

Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(209d) Step-1: Preparation of(−)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(209a)

Compound (209a) was prepared from3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (3.98 g, 22.69 mmol)and (R)-2-methylpropane-2-sulfinamide (2.5 g, 20.63 mmol) according tothe procedure described in step-1 of scheme 208 for preparation ofcompound 208a to afford(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(209a) (2.5 g, 8.98 mmol, 43.5% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.24 (d,J=8.1 Hz, 1H), 7.53 (dd, J=8.1, 4.8 Hz, 1H), 3.40 (m, 1H), 3.30 (m, 1H),1.47 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.82-0.66 (m, 1H), 0.44-0.29 (m,2H), 0.12-0.01 (m, 2H); Optical Rotation [α]_(D)=(−) 17.29 [0.59, MeOH].

Step-2: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(209b)

To a stirred solution of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(209a) (82 g, 295 mmol) in Toluene (1700 mL) at −20° C. was addeddropwise a freshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (920 mL,736 mmol) over a period of 120 mins. The reaction mixture was stirred at−20° C. for 1 h and quenched with 1N aqueous KHSO₄ (1600 mL). Thereaction mixture was stirred for 1 h at room temperature, basified with2 N NaOH to pH˜8 and extracted with ethyl acetate (1500, 700 mL). Theorganic layers were combined washed with water (2×700 mL), brine (700mL), dried and concentrated in vacuum. The crude residue was purified byflash column chromatography (silica gel, eluting with (9:1) ethylacetate/methanol in hexanes 0 to 50%) to afford(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(209b) (54.155 g, 139 mmol, 47.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.53-8.48 (m, 1H), 8.39 (dd, J=4.7, 1.5 Hz, 1H), 7.70(dt, J=8.1, 2.0 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 6.90 (dd, J=11.2,8.5 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.56-6.45 (m, 1H), 5.26 (s,1H), 5.10 (s, 2H), 2.67-2.54 (m, 2H), 1.28-1.11 (m, 1H), 1.12 (s, 9H),0.91 (m, 1H), 0.64 (m, 1H), 0.40-0.30 (m, 2H), −0.02-−0.14 (m, 2H); 19FNMR (282 MHz, DMSO d6) 6-137.67; MS (ES+) 390.4 (M+1); (ES−) 388.4(M−1); Optical Rotation [α]_(D)=(−) 105.71 [0.28, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(209c)

Compound (209c) was prepared using1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (21.76 g, 56.5 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(209b) (20 g, 51.3 mmol) using procedure as reported in step-3 of scheme208 for preparation of compound 208c to afford tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(209c) (16 g, 21.4 mmol, 41.2% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.41 (dd, J=4.7, 1.5Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.63-7.15 (m, 10H), 5.57 (s, 1H), 4.18(d, J=6.3 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.22-1.01 (m, 1H),1.12 (s, 9H), 1.00-0.80 (m, 1H), 0.72-0.54 (m, 1H), 0.40-0.28 (m, 2H),−0.02-−0.16 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −60.61, −122.92; MS(ES+) 757.6 (M+1); (ES−) 755.6 (M−1); Optical Rotation [α]_(D) (−) 66.4[0.25, MeOH].

Step-4: Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(209d)

To a stirred solution of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(209c) (15.76 g, 20.82 mmol) in ethanol (720 mL) was added conc.hydrochloric acid (17.40 mL, 209 mmol) and heated at reflux for 1 h. Thereaction mixture was concentrated in vacuum to dryness and the residueobtained was dissolved in ethanol (50 mL), triturated with t-butylmethyl ether (300 mL, 200 mL), and decanted. The solid was dried undervacuum, dissolved in water (100 mL) and concentrated in vacuum. Theoff-white solid was again dissolved in water (30 mL) and concentratedunder vacuum to dryness to afford(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(209d) (11.966 g) HCl salt as an of white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.87 (s, 1H), 9.73 (s, 3H), 8.80-8.73 (m, 2H), 8.63-8.38 (m,3H), 8.21 (dt, J=8.5, 1.7 Hz, 1H), 7.81 (dd, J=8.2, 5.2 Hz, 1H),7.75-7.32 (m, 8H), 4.09 (q, J=5.8 Hz, 2H), 2.71-2.37 (m, 2H), 1.22-1.04(m, 2H), 0.74-0.58 (m, 1H), 0.48-0.25 (m, 2H), 0.08-−0.15 (m, 2H); 19FNMR (282 MHz, DMSO-d₆) δ −60.63, −120.00; MS (ES+): 553.5 (M+1); OpticalRotation [α]_(D)=(−) 2.82 [1.065, MeOH]; Chiral purity checked byperforming chiral HPLC using chiral AD-H column, 1 mL/min, Solvent: 85%Hexane, 20% EtOH, 0.1% TEA, UV=260 nM, 20° C. (>99.99 ee).

Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(210d) Step-1: Preparation(+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(210a)

Compound (210a) was prepared from 3-cyclopropyl-1-phenylpropan-1-one(46d) (3.95 g, 22.69 mmol) using (S)-2-methylpropane-2-sulfinamide (2.5g, 20.63 mmol), using procedure as reported in step-1 of scheme 208 toafford(+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(210a) (1.22 g, 4.40 mmol, 21.32% yield) as a light brownish yellowsyrup; ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=7.4 Hz, 2H), 7.61-7.42 (m,3H), 3.36 (m, 1H), 3.31-3.13 (m, 1H), 1.46 (q, J=7.4 Hz, 2H), 1.23 (s,9H), 0.76 (m, 1H), 0.38 (m, 2H), 0.05 (m, 2H); MS (ES+) 278.2 (M+1),300.3 (M+Na), 555.4 (2M+1), 577.4 (2M+Na); Optical Rotation [α]_(D)=(+)22.22 [0.27, MeOH].

Step-2: Preparation of(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(210b)

Compound (210b) was prepared from(+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(210a) (2 g, 7.21 mmol)), using procedure as reported in step-2 ofscheme 208 to afford(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(210b) (2.16 g, 5.56 mmol, 77% yield) as light yellow syrup.

¹H NMR (300 MHz, DMSO-d₆) δ 7.36-7.24 (m, 4H), 7.23-7.15 (m, 1H), 6.87(dd, J=11.3, 8.5 Hz, 1H), 6.71 (dd, J=8.9, 2.4 Hz, 1H), 6.48 (ddd,J=8.5, 4.3, 2.3 Hz, 1H), 5.06 (s, 2H), 4.94 (s, 1H), 2.57 (m, 2H), 1.06(s, 10H), 1.05 (m, 1H), 0.87 (m, 1H), 0.45-0.24 (m, 2H), 0.04-−0.19 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −138.17; MS (ES+) 389.3 (M+1), 777.6(2M+1), 799.6 (2M+23), (ES−) 387.3 (M−H); Optical Rotation [α]_(D)=(+)112.56 [0.215, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(210c)

Compound (210c) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (1.473 g, 3.82 mmol) and(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(210b) (1.35 g, 3.47 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(210c) (1.532 g, 2.027 mmol, 58.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.63-7.16 (m, 13H), 5.29 (s, 1H), 4.19(d, J=6.2 Hz, 2H), 2.57 (m, 2H), 1.38 (s, 10H), 1.12 (s, 10H), 0.87 (m,1H), 0.62 (m, 1H), 0.43-0.23 (m, 2H), −0.09 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.79, −123.61; MS (ES+) 756.6 (M+1), 778.6 (M+Na); OpticalRotation [α]_(D)=(+) 72.14 [0.28, MeOH].

Step-4: Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(210d)

Compound (210d) free base was prepared from tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(210c) (1.454 g, 1.924 mmol) as reported in step-4 of scheme 208 toafford(−)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(210d) (0.830 g, 1.505 mmol, 78% yield) free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.55 (d, J=14.1 Hz, 3H),7.49-7.31 (m, 5H), 7.30-7.21 (m, 3H), 7.21-7.09 (m, 2H), 3.81 (s, 2H),3.34 (s, 2H), 2.73-2.55 (m, 2H), 2.31-2.10 (m, 2H), 1.03 (m, 2H), 0.61(m, 1H), 0.43-0.23 (m, 2H), −0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.66, −124.51; MS (ES−) 550.4 (M−1).

To a stirred solution of(−)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(210d) (682 mg, 1.236 mmol) free base in ethanol (10 mL) was added conc.HCl (0.515 mL, 6.18 mmol), water (5 mL) stirred for 10 mins andconcentrated in vacuum to dryness to afford(−)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(210d) (666 mg, 1.066 mmol, 86% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.82 (s, 1H), 9.29 (s, 3H), 8.51 (s,3H), 7.72 (dd, J=5.4, 3.6 Hz, 2H), 7.63 (dt, J=7.2, 1.7 Hz, 1H),7.60-7.47 (m, 3H), 7.47-7.30 (m, 7H), 4.11 (s, 2H), 2.41-2.55 (m, 2H),1.22-0.99 (m, 2H), 0.67 (m, 1H), 0.46-0.28 (m, 2H). 0.01-0.05 (m, 2H);19F NMR (282 MHz, DMSO-d₆) δ −60.81, −120.90; MS (ES+) 550.4 (M−1),586.4 (M+Cl); Optical Rotation [α]_(D)=(−) 3.51 [1.025, MeOH]; Analysiscalculated for C₃₀H₂₉F₄N₅O.2HCl.1.5H₂O: C: 55.36, H: 5.27, N: 10.76, Cl:11.68; Found: C: 55.35, H: 5.45, N: 10.63, Cl: 11.45.

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(211d) Step-1: Preparation(−)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(211a)

Compound (211a) was prepared from 3-cyclopropyl-1-phenylpropan-1-one(46d) (3.95 g, 22.69 mmol) and (R)-2-methylpropane-2-sulfinamide (2.5 g,20.63 mmol), using procedure as reported in step-1 of scheme 208 toafford(−)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(211a) (3.247 g, 11.70 mmol, 56.7% yield) as a light brownish yellowsyrup; ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=7.6 Hz, 2H), 7.51 (qd,J=8.7, 7.8, 3.6 Hz, 3H), 3.45-3.15 (m, 2H), 1.46 (m, 2H), 1.23 (s, 9H),0.82-0.67 (m, 1H), 0.43-0.32 (m, 2H), 0.06 (m, 2H); MS (ES+) 278.3(M+1), 300.3 (M+Na), 577.5 (2M+Na); Optical Rotation [α]_(D)=(−) 36.32[0.76, CHCl₃].

Step-2: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(211b)

Compound (211b) was prepared from(−)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide(211a) (3.065 g, 11.05 mmol), using procedure as reported in step-2 ofscheme 208 to afford(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(211b) (2.62 g, 6.74 mmol, 61.0% yield) as a light brown oil; ¹H NMR(300 MHz, DMSO-d₆) δ 7.35-7.25 (m, 4H), 7.22-7.15 (m, 1H), 6.87 (dd,J=11.3, 8.5 Hz, 1H), 6.71 (dd, J=8.8, 2.4 Hz, 1H), 6.49 (m, 1H), 5.06(s, 2H), 4.94 (s, 1H), 2.61-2.52 (m, 2H), 1.14 (m, 10H), 0.97-0.80 (m,1H), 0.75-0.52 (m, 1H), 0.36 (m, 2H), −0.01-−0.16 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −138.17; MS (ES+) 389.4 (M+1), 777.6 (2M+1), 799.6(2M+Na); Optical Rotation [α]_(D)=(−) 100.41 [0.245, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(211c)

Compound (211c) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (2.73 g, 7.08 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(211b) (2.5 g, 6.43 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(211c) (1.532 g, 2.027 mmol, 31.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.57 (d, J=6.9 Hz, 2H), 7.53-7.47 (m,1H), 7.42 (dd, J=5.7, 2.8 Hz, 2H), 7.39-7.15 (m, 9H), 5.29 (s, 1H), 4.19(d, J=6.3 Hz, 2H), 2.77-2.55 (m, 2H), 1.38 (s, 9H), 1.12 (s, 9H), 1.05(s, 1H), 0.96-0.80 (m, 1H), 0.62 (m, 1H), 0.43-0.26 (m, 2H), −0.02-−0.17(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.79, −123.62; MS (ES+) 756.6(M+H), 778.5 (M+Na), (ES−) 754.5 (M−H), 790.4 (M+Cl); Optical Rotation[α]_(D)=(−) 72.94 [0.255, MeOH].

Step-4: Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(211d)

Compound (211d) free base was prepared from of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(211c) (1.49 g, 1.971 mmol) as reported in step-4 of scheme 208 toafford(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(211d) (1.0 g, 1.813 mmol, 92% yield) free base as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.32 (s, 2H), 7.57 (d, J=5.1 Hz,2H), 7.50 (s, 1H), 7.47-7.40 (m, 2H), 7.39-7.30 (m, 2H), 7.29-7.22 (m,2H), 7.20-7.10 (m, 2H), 3.77 (s, 2H), 3.35 (s, 2H), 2.29-1.97 (m, 4H),1.10-0.94 (m, 2H), 0.62 (m, 1H), 0.39-0.28 (m, 2H), −0.09 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.72, −124.61; MS (ES+) 552.4 (M+1), (ES−)550.4 (M−1).

To a stirred solution of(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(211d) (0.9 g, 1.632 mmol) free base in ethanol (10 mL) was added conc.HCl (0.680 mL, 8.16 mmol), water (5 mL) stirred for 10 mins andconcentrated to dryness to afford(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(211d) (700 mg, 1.121 mmol, 68.7% yield) hydrochloride salt as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (d, J=4.1 Hz, 1H), 9.38 (d, J=33.2 Hz,3H), 8.55 (s, 3H), 7.72 (dd, J=4.6, 2.8 Hz, 2H), 7.68-7.61 (m, 1H),7.60-7.47 (m, 3H), 7.45-7.31 (m, 7H), 4.10 (s, 2H), 2.3-2.6 (m, 2H),1.09 (m, 2H), 0.68 (m, 1H), 0.36 (m, 2H), −0.01 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.63, −120.68; MS(ES−) 550.4, 586.4 (M+Cl);[α]_(D)=(+) 4.77 [1.09, MeOH]; Analysis calculated forC₃₀H₂₉F₄N₅O.2HCl.1.75H₂O: C, 54.92; H, 5.30; N, 10.68; Cl, 10.81; Found:C: 54.76, H: 5.33, N: 10.52, Cl: 11.04.

Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(212g) Step: 1 Preparation of (E)-4-(3-cyclopropylacryloyl)benzonitrile(212b)

To a stirred solution of 4-acetylbenzonitrile (212a) (5 g, 34.4 mmol) inethanol (100 mL) at 0° C. was added cyclopropanecarboxaldehyde (4.15 mL,55.1 mmol) followed by potassium hydroxide (2 M aqueous solution, 3.44mL, 6.89 mmol). The reaction mixture allowed to attain room temperatureand stirred for 24h. The reaction was acidified with HCl to pH-6 andconcentrated in vacuum maintaining bath temperature below 35° C. Theresidue obtained was purified by flash column chromatography (silica geleluting with ethyl acetate in hexanes 0 to 20%) to afford(E)-4-(3-cyclopropylacryloyl)benzonitrile (212b) (512 mg, 2.60 mmol,7.54% yield) as a colorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ8.12-8.08 (m, 2H), 8.02-7.99 (m, 2H), 7.25 (d, J=15.0 Hz, 1H), 6.57 (dd,J=15.1, 10.4 Hz, 1H), 1.80 (dddd, J=12.4, 10.4, 7.9, 4.5 Hz, 1H),1.08-0.99 (m, 2H), 0.79 (tt, J=4.8, 2.4 Hz, 2H); MS (ES−) 196.1 (M−1).

Step 2: Preparation of 4-(3-cyclopropylpropanoyl)benzonitrile (212c)

To a stirred solution of (E)-4-(3-cyclopropylacryloyl)benzonitrile(212b) (1.1 g, 5.58 mmol) in acetonitrile (10 mL) was addedtri-n-butyltin hydride (1.489 mL, 5.58 mmol) and heated at reflux for 6h. The reaction mixture was cooled to room temperature and concentratedin vacuum. The residue obtained was purified by flash columnchromatography (silica gel eluting with ethyl acetate in hexanes 0 to100%) to afford 4-(3-cyclopropylpropanoyl)benzonitrile (212c) (457 mg,2.294 mmol, 41.1% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.08-8.03 (m, 2H), 7.98-7.91 (m, 2H), 3.09 (t, J=7.2 Hz, 2H), 1.46 (q,J=7.1 Hz, 2H), 0.77-0.59 (m, 1H), 0.38-0.26 (m, 2H), 0.06-−0.04 (m, 2H);MS (ES−) 198.2 (M−1).

Step-3: Preparation of(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(212d)

Compound (212d) was prepared from 4-(3-cyclopropylpropanoyl)benzonitrile(212c) (0.814 g, 4.08 mmol) and (R)-2-methylpropane-2-sulfinamide (0.45g, 3.71 mmol), using procedure as reported in step-1 of scheme 208 toafford(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(212d) (720 mg, 2.38 mmol, 64.1% yield) as a light yellow syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 8.11-7.93 (m, 4H), 3.34 (m, 2H), 1.44 (m, 1H), 1.24(s, 10H), 0.73 (m, 1H), 0.45-0.29 (m, 2H), 0.03 (m, 2H).; Opticalrotation: [α]_(D)=(+) 16.55 [0.29, MeOH].

Step-4: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e)

Compound (212e) was prepared from(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(212d) (0.5 g, 1.653 mmol), using procedure as reported in step-2 ofscheme 208 to afford(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (538 mg, 1.301 mmol, 79% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.83-7.66 (m, 2H), 7.61-7.44 (m, 2H), 6.90 (dd, J=11.3,8.5 Hz, 1H), 6.70 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.6, 4.3, 2.4Hz, 1H), 5.27 (s, 1H), 5.11 (s, 2H), 2.62-2.55 (m, 1H), 2.46-2.39 (m,1H), 1.12 (s, 9H), 1.06 (s, 1H), 0.99-0.80 (m, 1H), 0.64 (s, 1H), 0.36(m, 2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.54; MS(ES+) 414.396 (M+1); Optical rotation: [α]_(D)=(−) 83.24 [0.185, MeOH].

Step-5: Preparation of tert-butyl3-(5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(212f)

Compound (212f) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.512 g, 1.330 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (0.5 g, 1.209 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(212f) (557 mg, 0.713 mmol, 59.0% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.58 (m,2H), 7.49 (m, 2H), 7.42 (m, 2H), 7.38-7.30 (m, 2H), 7.24 (d, J=7.8 Hz,2H), 5.57 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.10-2.95 (m, 1H), 2.65-2.54(m, 1H), 2.44 (m, 1H), 1.38 (s, 9H), 1.12 (s, 10H), 1.03-0.76 (m, 1H),0.62 (m, 1H), 0.34 (m, 2H), −0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.78, −122.98; MS (ES+) 803.6 (M+Na); Optical rotation: [α]_(D)=(−) 56[0.15, MeOH].

Step-6: Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(212g)

To a stirred solution of tert-butyl3-(5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(212f) (0.51 g, 0.653 mmol) in ethanol (25 mL) was added conc. HCl(0.544 mL, 6.53 mmol) and heated at reflux for 1 h. The reaction mixturewas concentrated in vacuum to dryness, triturated with ether, stirredovernight at room temperature, collected by filtration and washed withether. This residue was dissolved in ethanol (20 mL) and concentrated invacuum to dryness to afford of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(212g) (410 mg, 0.631 mmol, 97% yield) hydrochloride as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H), 9.48 (s, 3H), 8.43 (s, 3H),7.94 (d, J=8.0 Hz, 2H), 7.71 (d, J=12.1 Hz, 2H), 7.66-7.46 (m, 6H),7.45-7.28 (m, 2H), 4.12 (s, 2H), 2.60-2.49 (m, 2H), 1.29-1.08 (m, 2H),0.67 (m, 1H), 0.46-0.29 (m, 2H), 0.02-001 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.79, −120.37; MS (ES+) 577.4 (M+1), (ES−) 575.5 (M−1),611.4 (M+Cl); Optical rotation: [α]_(D)=(+) 16.43 [CH₃OH, 0.28];Analysis calculated for C₃₁H₂₈F₄N₆O.2HCl.2H₂O: C, 54.31; H, 5.00; Cl,10.34; N, 12.26; Found: C, 53.95; H, 5.01; Cl, 9.94; N, 12.01.

Preparation of(−)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(213d) Step-1: Preparation of(−)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(213a)

Compound (213a) was prepared from 4-(3-cyclopropylpropanoyl)benzonitrile(212c) (1.21 g, 6.07 mmol) and (S)-2-methylpropane-2-sulfinamide (0.743g, 6.07 mmol), using procedure as reported in step-1 of scheme 208 toafford(−)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(213a) (1.252 g, 4.14 mmol, 68.2% yield) as a light yellow syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 8.04-7.89 (m, 4H), 3.47-3.16 (m, 2H), 1.41 (q,J=7.5 Hz, 2H), 1.21 (s, 9H), 0.80-0.60 (m, 1H), 0.40-0.27 m, 2H),0.08-−0.10 (m, 2H); MS (ES+) 303.3 (M+1); (ES−) 301.3 (M−1).

Step-2: Preparation of(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(213b)

Compound (213b) was prepared from(−)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(213a) (1.197 g, 3.96 mmol), using procedure as reported in step-2 ofscheme 208 to afford(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(213b) (968 mg, 2.341 mmol, 59.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.80-7.73 (m, 2H), 7.55-7.49 (m, 2H), 6.89 (dd, J=11.3,8.5 Hz, 1H), 6.71 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4Hz, 1H), 5.23 (s, 1H), 5.09 (s, 2H), 2.65-2.40 (m, 2H), 1.13 (s, 9H),1.25-1.00 (m, 1H), 1.00-0.80 (m, 1H), 0.72-0.55 (m, 1H), 0.45-0.25 (m,2H), 0.04-−0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.37; MS (ES+);436.3 (M+Na); Optical rotation: [α]_(D)=(+) 104.62 [0.295, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((+)-1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(213c)

Compound (213c) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.933 g, 2.42 mmol) and(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(213b) (0.91 g, 2.2 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((+)-1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(213c) (1.126 g, 1.442 mmol, 65.5% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.93-7.09 (m, 13H), 5.58 (s, 1H),4.19 (d, J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.13 (s, 9H),1.20-1.00 (m, 1H), 0.87 (d, J=23.9 Hz, 1H), 070-0.55 (m, 1H), 0.43-0.26(m, 2H), −0.01-−0.18 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −61.16,−122.81; MS (ES+) 781.6 (M+1); ES (−) 779.5 (M−1) Optical rotation:[α]_(D)=(+) 65.38 [0.26, MeOH].

Step-4: Preparation of(−)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(213d)

To a stirred solution of tert-butyl3-(5-(5-((+)-1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(213c) (0.609 g, 0.78 mmol) in ethanol (6 mL) was added conc. HCl (0.65mL, 7.8 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and purified by flash columnchromatography (silica gel, 25 g, eluting with CMA-80 in chloroform0-25%) to furnish product. The product was dissolved in methanol (10 mL)and added 4 N aqueous HCl (0.52 mL) and concentrated in vacuum todryness to afford(−)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(213d) (330 mg, 0.508 mmol, 65.1% yield) hydrochloride salt as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H), 9.48 (s, 3H), 8.42 (s, 3H),7.94 (d, J=8.4 Hz, 2H), 7.75-7.66 (m, 2H), 7.64-7.46 (m, 6H), 7.40 (t,J=9.3 Hz, 1H), 7.36-7.28 (m, 1H), 4.11 (q, J=5.8 Hz, 2H), 2.55 (d, J=9.7Hz, 2H), 1.22-0.99 (m, 2H), 0.77-0.53 (m, 1H), 0.44-0.26 (m, 2H), −0.00(s, 2H); ¹⁹F NMR (282 MHz, DMSO d₆) δ −60.64, −120.16. MS (ES+) 577.5(M+1); (ES−) 576.8 (M−1); IR 2234 cm⁻¹; Optical rotation: [α]_(D)=(−)10.84 [1.07, MeOH].

Preparation of(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g) Step: 1 Preparation of 3-(3-cyclopropylacryloyl)benzonitrile(214b)

To a stirred solution of 3-acetylbenzonitrile (214a) (50 g, 344 mmol) inmethanol (800 mL) at 0° C. was added cyclopropanecarboxaldehyde (41 mL,549 mmol) followed by potassium hydroxide (1M aqueous solution, 67 mL,67 mmol). The reaction mixture allowed to attain room temperature andstirred for 14h. The reaction was acidified with HCl to pH-6 (75 mL, 1N) and concentrated in vacuum maintaining bath temperature below 35° C.The residue was diluted with ethyl acetate (1200 mL) and washed withwater (800 mL). The aqueous layer was extracted with ethyl acetate (800mL) and organic layers were combined washed with brine, dried, filteredand concentrated in vacuum to afford3-(3-cyclopropylacryloyl)benzonitrile (214b) (72.42 gm) crude as acolorless liquid, which was used as such in next step; ¹H NMR (300 MHz,DMSO-d₆) δ 8.19 (dp, J=7.8, 1.6 Hz, 1H), 8.11 (dddt, J=6.3, 3.7, 2.6,1.4 Hz, 1H), 7.80-7.65 (m, 2H), 7.32 (dd, J=15.1, 7.6 Hz, 1H), 6.60(ddd, J=15.0, 11.3, 10.4 Hz, 1H), 1.91-1.74 (m, 1H), 1.04 (m, 2H),0.85-0.75 (m, 2H).

Step 2: Preparation of 3-(3-cyclopropylpropanoyl)benzonitrile (214c)

To a stirred solution of 3-(3-cyclopropylacryloyl)benzonitrile (214b)(65.7 g, 333 mmol) in benzene (750 mL) was added tri-n-butyltin hydride(185 mL, 666 mmol) and heated at reflux for 14 h. The reaction mixturewas cooled to room temperature and concentrated in vacuum. The residuewas purified by flash column chromatography (silica gel eluting withethyl acetate in hexanes 0 to 100%) to afford3-(3-cyclopropylpropanoyl)benzonitrile (214c) (23.3, 116.9 mmol, 34%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (td, J=1.8,0.6 Hz, 1H), 8.24 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 8.09 (dt, J=7.7, 1.4Hz, 1H), 7.73 (td, J=7.8, 0.6 Hz, 1H), 3.15 (t, J=7.2 Hz, 2H), 1.52 (q,J=7.1 Hz, 2H), 0.81-0.64 (m, 1H), 0.46-0.26 (m, 2H), 0.13-0.00 (m, 2H);MS (ES−) 198.2 (M−1).

Step-3: Preparation of(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(214d)

Compound (214d) was prepared from 3-(3-cyclopropylpropanoyl)benzonitrile(214c) (22.8 g, 114 mmol) and (R)-2-methylpropane-2-sulfinamide (13.95g, 114 mmol), using procedure as reported in step-1 of scheme 208 toafford(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(214d) (21.8 g, 72.1 mmol, 63% yield) as a light yellow syrup;

¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 8.21-8.12 (m, 1H), 8.01 (d,J=7.7 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 3.54-3.13 (m, 2H), 1.44 (q, J=7.5Hz, 2H), 1.23 (s, 9H), 0.82-0.65 (m, 1H), 0.44-0.29 (m, 2H), 0.11-0.00(m, 2H); MS (ES+) 303.3 (M+1); (ES−) 301.3 (M−1); Optical rotation:[α]_(D) (−) 66.92 (0.26, MeOH).

Step-4: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e)

To a stirred solution of(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(214d) (17.72 g, 58.6 mmol) in toluene (350 mL) at −20° C. was addeddropwise a freshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(160 mL, 120 mmol, 0.75N) over a period of 30 mins. The reaction mixturewas stirred at −20° C. for 1 h and quenched with 1N aqueous KHSO₄ (275mL). The reaction mixture was stirred for 1 h at room temperature,diluted with water (100 mL) basified with 2 N NaOH to pH 8 and extractedwith ethyl acetate (600 mL, 300 mL). The organic layers were combinedwashed with water (2×300 mL), brine (300 mL), dried and concentrated invacuum to dryness. The crude residue was triturated with ethyl acetateand solid obtained was collected by filtration to obtain on drying undervacuum(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (10.4 g, 42.91% yield) as a white solid. The filtrate wasconcentrated in vacuum and purified by flash column chromatography(silica gel, eluting with ethyl acetate in hexanes 0 to 50%) to(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (4.11 g, 16.95% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.78 (t, J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.4 Hz, 1H), 7.62(dt, J=8.1, 1.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.90 (dd, J=11.3, 8.5Hz, 1H), 6.72 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4 Hz,1H), 5.27 (s, 1H), 5.10 (s, 2H), 2.66-2.40 (m, 2H), 1.20-1.03 (m, 1H),1.12 (s, 9H), 1.01-0.81 (m, 1H), 0.72-0.57 (m, 1H), 0.36 (m, 2H),0.03-0.15 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −137.34; MS (ES+): 436.4(M+Na); IR (KBr) 2235 cm⁻¹; Optical rotation: [α]_(D) (−) 107.95 (0.78,MeOH); Analysis calculated for C₂₃H₂₈FN₃OS: C, 66.80; H, 6.82; N, 10.16;Found: C, 67.06; H, 6.82; N, 10.28.

Step-5: Preparation of tert-butyl3-(5-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(214f)

Compound (214f) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (9.74 g, 25.3 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (9.5 g, 22.97 mmol) using the procedure as reported in step-3 ofscheme 208 to afford of tert-butyl3-(5-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(214f) (10.00 g, 12.8 mmol, 55.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.78 (s, 1H), 7.71 (dt, J=7.3, 1.4 Hz,1H), 7.64-7.30 (m, 8H), 7.23 (d, J=7.5 Hz, 2H), 5.56 (s, 1H), 4.18 (d,J=6.2 Hz, 2H), 2.74-2.39 (m, 2H), 1.38 (s, 9H), 1.12 (s, 9H), 1.09-0.82(m, 2H), 0.72-0.54 (m, 1H), 0.34 (d, J=8.0 Hz, 2H), −0.01-−0.16 (m, 2H);¹⁹F NMR (282 MHz, DMSO) δ −60.80, −122.94; MS (ES+) 803.6 (M+Na), (ES−)779.6 (M−1); Optical rotation: [α]_(D)=(−) 75.09 (0.285, MeOH).

Step-6: Preparation of(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g)

To a stirred solution of tert-butyl3-(5-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(214f) (0.75 g, 0.960 mmol) in ethanol (7.5 mL) was added conc. HCl (0.8mL, 9.6 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was purifiedby flash column chromatography (silica gel, 24 g eluting with CMA 80 inchloroform 0 to 100%) to afford product which was repurified by flashcolumn chromatography (silica gel, 24 g eluting with methanol inchloroform 0 to 50%) to afford(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g) (0.36 g, 0.624 mmol, 65.0% yield) free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.86 (t, J=1.7 Hz, 1H),7.70-7.55 (m, 5H), 7.54-7.43 (m, 3H), 7.39 (dt, J=7.2, 2.0 Hz, 1H), 7.28(ddd, J=8.7, 4.8, 2.4 Hz, 1H), 7.18 (dd, J=10.2, 8.7 Hz, 1H), 3.92 (s,2H), 2.23 (t, J=8.2 Hz, 2H), 1.08-0.94 (m, 2H), 0.62 (qq, J=7.0, 4.7,3.5 Hz, 1H), 0.40-0.27 (m, 2H), −0.08 (td, J=5.2, 4.6, 3.4 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO) δ −60.39, −123.77; MS (ES+) 577.5 (M+1); (ES−) 575.5(M−1); IR (KBr) 2230 cm⁻¹; Optical rotation: [α]_(D)=(+) 9.18 [1.59,MeOH].

To a stirred solution of free base of(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g) (0.3 g, 0.52 mmol) in methanol (10 mL) was added conc. HCl (0.217mL, 2.60 mmol) stirred for 30 mins and concentrated to dryness to afford(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g) (0.31 g, 0.477 mmol, 92% yield) hydrochloride as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H), 9.49 (s, 3H), 8.46 (s, 3H),7.93-7.80 (m, 1H), 7.74-7.68 (m, 3H), 7.67-7.49 (m, 5H), 7.44-7.29 (m,2H), 4.11 (d, J=3.8 Hz, 2H), 2.55 (d, J=10.8 Hz, 3H), 1.37-1.16 (m, 1H),0.67 (q, J=6.5 Hz, 1H), 0.47-0.25 (m, 2H), 0.07-−0.02 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.64, −120.22; MS (ES+) 577.4 (M+1); (ES−) 575.5(M−1); IR (KBr) 2235 cm⁻¹.

Preparation of(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(215d) Step-1: Preparation of(+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(215a)

Compound (215a) was prepared from 3-(3-cyclopropylpropanoyl)benzonitrile(212c) (2.33 g, 11.69 mmol) and (S)-2-methylpropane-2-sulfinamide (1.432g, 11.69 mmol), using procedure as reported in step-1 of scheme 208 toafford(+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(215a) (2.186 g, 7.23 mmol, 61.8% yield) as a light yellow syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.02 (d,J=7.7 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 3.54-3.13 (m, 2H), 1.45 (q, J=7.5Hz, 2H), 1.24 (s, 9H), 0.85-0.65 (m, 1H), 0.43-0.27 (m, 2H), 0.13-−0.09(m, 2H); MS (ES+) 303.3 (M+1); 325.3 (M+Na) Optical rotation:[α]_(D)=(+) 27.74 [0.31, MeOH].

Step-2: Preparation of(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(215b)

Compound (215b) was prepared from(+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(215a) (0.93g, 3.08 mmol), using procedure as reported in step-2 ofscheme 208 to afford(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(215b) (370 mg, 0.895 mmol, 29.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.78 (t, J=1.7 Hz, 1H), 7.70 (dt, J=7.5, 1.3 Hz, 1H),7.62 (dt, J=8.2, 1.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.90 (dd, J=11.3,8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.47 (ddd, J=8.6, 4.4, 2.4Hz, 1H), 5.26 (s, 1H), 5.10 (s, 2H), 2.65-2.40 (m, 2H), 1.30-1.00 (m,1H), 1.12 (s, 9H), 1.00-0.80 (m, 1H), 0.72-0.56 (m, 1H), 0.42-0.28 (m,2H), 0.06-−0.14 (m, 2H); MS (ES+) 414.4 (M+1); 436.4 (M+Na) (ES−) 412.4(M−1); Optical rotation: [α]_(D)=(+) 101.13 [0.265, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(215c)

Compound (215c) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (321 mg, 0.833 mmol) and(S)—N-((+)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(215b) (313 mg, 0.757 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(215c) (358 mg, 458 mmol, 60.6% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.62 (s, 1H), 7.78 (bs, 1H), 7.72 (dt, J=7.4, 1.4 Hz,1H), 7.63-7.32 (m, 9H), 7.24 (d, J=7.6 Hz, 2H), 5.58 (s, 1H), 4.19 (d,J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.20-1.00 (m, 1H), 1.12(s, 9H), 0.97-0.79 (m, 1H), 0.70-0.55 (m, 1H), 0.42-0.24 (m, 2H),0.01-−0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −61.11, −122.89; MS(ES+) 781.6 (M+1); 803.6 (M+Na), ES (−) 779.6 (M−1) Optical rotation:[α]_(D)=(+) 75.29 [0.255, MeOH].

Step-4: Preparation of(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(215d)

To a stirred solution of tert-butyl3-(5-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(215c) (0.152 g, 0.195 mmol) in ethanol (15 mL) was added conc. HCl(0.16 mL, 1.917 mmol) and heated at reflux for 1 h. The reaction mixturewas concentrated in vacuum to dryness and residue was triturated witht-butyl methyl ether (2×20 mL) and decanted. The solid was dried undervacuum, dissolved in water (5 mL) and concentrated in vacuum to drynessto afford(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(215d) (96 mg) hydrochloride salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.78 (s, 1H), 9.40 (s, 3H), 8.35 (s, 3H), 7.92-7.82 m, 2H),7.74-7.23 (m, 10H), 4.13 (s, 2H), 2.60-2.40 (m, 2H), 1.20-0.95 (m, 2H),0.75-0.60 (m, 1H), 0.42-0.32 (m, 2H), 0.05 to −0.05 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.64, −120.25; MS (ES+): 599.5 (M+Na); Opticalrotation: [α]_(D)=(−) 7.84 [0.255, methanol]; Analysis calculated forC₃₁H₂₈F₄N₆O.2HCl.2.5H₂O: C, 53.61; H, 5.08; Cl, 10.21; N, 12.10; Found:C, 53.49; H, 4.92; Cl, 10.21; N, 11.77.

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(216d) Step-1: Preparation of(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(216a)

Compound (216a) was prepared from3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (92d) (1.8 g, 10.27 mmol) and(R)-2-methylpropane-2-sulfinamide (1.566 g, 12.84 mmol) using procedureas reported in step-1 of scheme 208 to afford(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(216a) (1.838 g, 6.57 mmol, 63.9% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 8.76-8.69 (m, 2H), 7.80-7.73 (m, 2H), 3.49-3.15 (m, 2H),1.45 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.84-0.65 (m, 1H), 0.43-0.30 (m,2H), 0.10-−0.03 (m, 2H); MS (ES+) 301.3, (M+Na); (ES−) 277.3 (M−1);Optical Rotation [α]_(D)=(−) 27.61 [0.355, MeOH].

Step-2: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b)

Compound (216b) was prepared from(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(216a) (1.7 g, 6.11 mmol), using procedure as reported in step-2 ofscheme 208 to afford(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b) (1.443 g, 3.7 mmol, 60.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.77-8.68 (m, 2H), 7.62-7.53 (m, 2H), 7.15 (dd, J=11.3,8.5 Hz, 1H), 7.00-6.94 (m, 1H), 6.77-6.70 (m, 1H), 5.50 (s, 1H), 5.35(s, 2H), 2.90-2.60 (m, 2H), 1.47-1.27 (m, 1H), 1.38 (s, 9H), 1.25-1.05(m, 1H), 0.97-0.80 (m, 1H), 0.65-0.55 (m, 2H), 0.32-0.10 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) −137.30; MS (ES+): 390.4 (M+1); Chiral puritychecked by performing chiral HPLC using chiral AD-H column, 1 mL/min,Solvent: 90% Hexane, 10% EtOH, 0.1% TEA, UV=260 nM, 25° C. (>99.99 ee);Optical Rotation [α]_(D)=(−) 78.49 [0.265, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(216c)

Compound (216c) was prepared using1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.866 g, 2.246 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b) (700 mg, 1.797 mmol) using procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(216c) (688 mg, 0.909 mmol, 50.6% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.53-8.44 (m, 2H), 7.64-7.19 (m, 11H),5.57 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s, 9H),1.13 (s, 9H), 1.05-0.80 (m, 1H), 0.70-0.50 (m, 1H), 0.39-0.29 (m, 2H),−0.01-−0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.61, −122.74; MS(ES+) 757.6 (M+1); 779.6 (M+Na), (ES−) 755.6 (M−1); Optical Rotation[α]_(D) (−) 46.92 [0.26, MeOH].

Step-4: Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(216d)

To a stirred solution of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(216c) (627 mg, 0.828 mmol) in ethanol (30 mL) was added conc. HCl (0.69mL, 8.28 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and residue was dissolved in ethanol(5 mL) triturated with t-butyl methyl ether (2×20 mL) and decanted. Thesolid was dried under vacuum, dissolved in water (20 mL) andconcentrated in vacuum to dryness to afford(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(216d) (406 mg, 0.56 mmol, 67.6% yield) hydrochloride salt as an offwhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.74 (s, 3H),8.91-8.76 (m, 2H), 8.49 (d, J=7.1 Hz, 3H), 7.75-7.60 (m, 6H), 7.56 (d,J=7.9 Hz, 1H), 7.53-7.44 (m, 1H), 7.40 (dd, J=6.8, 2.3 Hz, 2H),4.16-4.07 (m, 2H), 2.60-2.54 (m, 2H), 1.33-1.15 (m, 1H), 1.14-0.96 (m,1H), 0.78-0.52 (m, 1H), 0.45-0.30 (m, 2H), 0.09-−0.05 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.63, −119.70; MS (ES+) 554.5 (M+1), 576.5(M+Na), (ES−) 587.5 (M+Cl); Analysis calculated forC₂₉H₂₈F₄N₆O.3HCl.3.5H₂O; C: 48.04, H: 5.28; N: 11.59: Found: C: 48.06;H: 5.39; N: 11.66; Optical Rotation [α]_(D)=(+) 12.43 [0.575, MeOH].

Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(217d) Step-1: Preparation of(+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(217a)

Compound (217a) was prepared from3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (92d) (1.0 g, 5.71 mmol) and(S)-2-methylpropane-2-sulfinamide (0.838 g, 6.85 mmol) using procedureas reported in step-1 of scheme 208 to afford(+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(217a) (0.973 g, 3.49 mmol, 61.2% yield) as a yellow syrup; ¹HNMR (300MHz, DMSO-d₆) δ 9.08-9.01 (m, 2H), 8.08 (m, 2H), 3.78-3.51 (m, 2H), 1.77(m, 2H), 1.57 (s, 9H), 1.06 (m, 1H), 0.7-0.65 (m, 2H), 0.43-0.23 (m,2H); MS (ES+) 279.3 (M+1); 301.3, (M+Na); (ES−) 277.4 (M−1); OpticalRotation [α]_(D)=(+) 33.96 [0.265, MeOH].

Step-2: Preparation of(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(217b)

Compound (217b) was prepared from(+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(217a) (0.928 g, 3.33 mmol), using procedure as reported in step-2 ofscheme 208 to afford(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(217b) (0.766 g, 1.966 mmol, 59% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.55-8.42 (m, 2H), 7.39-7.25 (m, 2H), 6.89 (dd, J=11.3,8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.48 (ddd, J=8.5, 4.4, 2.4Hz, 1H), 5.26 (s, 1H), 5.10 (s, 2H), 2.66-2.54 (m, 1H), 2.49-2.36 (m,1H), 1.13 (s, 9H), 1.12 (m, 1H), 0.92 (m Hz, 1H), 0.71-0.56 (m, 1H),0.42-0.27 (m, 2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−137.32; MS (ES+) 390.4 (M+1); (ES−) 388.5 (M−1); Chiral purity checkedby performing chiral HPLC using chiral AD-H column, 1 mL/min, Solvent:90% Hexane, 10% EtOH, 0.1% TEA, UV=260 nM, 25° C. (99.355% ee); OpticalRotation [α]_(D)=(+) 82.4 [0.25, MeOH].

Step-3: Preparation of tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(217c)

Compound (217c) was prepared using1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.61 g, 1.582 mmol) and(S)—N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(217b) (493 mg, 1.266 mmol) using procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(217c) (637 mg, 0.841 mmol, 66.48% yield) as a white semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.54-8.44 (m, 2H), 7.63-7.16 (m,11H), 5.58 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s,9H), 1.30-0.80 (m, 2H), 1.13 (s, 9H), 0.70-0.55 (m, 1H), 0.40-0.27 (m,2H), −0.01-−0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −122.85;MS (ES+) 757.6 (M+1); 779.6 (M+Na), (ES−) 755.5 (M−1); Optical Rotation[α]_(D) (+) 50.37 [0.27, MeOH].

Step-4: Preparation of(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(217d)

To a stirred solution of tert-butyl3-(5-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(217c) (119 mg, 0.157 mmol) in ethanol (10 mL) was added conc. HCl (0.13mL, 1.557 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and residue was dissolved in ethanol(5 mL) triturated with t-butyl methyl ether (30 mL) and decanted. Thesolid was dried under vacuum, dissolved in water (10 mL) andconcentrated in vacuum to dryness to afford(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(217d) (78 mg, 0.141 mmol, 90% yield) hydrochloride as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.63 (s, 3H), 8.84-8.73 (m, 2H),8.44 (s, 3H), 7.75-7.68 (m, 2H), 7.66-7.31 (m, 8H), 4.12 (q, J=6.0 Hz,2H), 2.60-2.40 (m, 2H), 1.35-0.93 (m, 2H), 0.79-0.56 (m, 1H), 0.45-0.28(m, 2H), 0.06 to −0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.63,−119.88; MS (ES+): 575.5 (M+Na); Optical Rotation [α]_(D)=(−) 10.32[0.32, MeOH]; Analysis calculated for C₂₉H₂₈F₄N₆O.3HCl.3.25H₂O; C,48.34; H, 5.25; N, 11.66: Found: C, 48.20; H, 5.31; N, 11.59.

Preparation of(+)-N-(3-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(218c) Step: 1 Preparation of(R)—N-((−)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(218a)

Compound (218a) was prepared from(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(212d) (2 g, 6.64 mmol), using procedure as reported in step-2 of scheme208 to afford(R)—N-((−)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(218a) (1.65 g, 4.17 mmol, 63.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.80-7.71 (m, 2H), 7.58-7.50 (m, 2H), 6.93 (t, J=7.8 Hz,1H), 6.50 (t, J=1.9 Hz, 1H), 6.48-6.43 (m, 1H), 6.41-6.35 (m, 1H), 5.15(s, 1H), 5.05 (s, 2H), 2.70-2.35 (m, 2H), 1.13 (s, 9H), 1.21-1.05 (m,1H), 1.00-0.8 (m, 1H), 0.72-0.55 (s, 1H), 0.45-0.21 (m, 2H), 0.07-−0.22(m, 2H); MS (ES+) 396.4 (M+1) 418.4 (M+Na); (ES−) 394.3 (M−1); Opticalrotation: [α]_(D)=(−) 103.57 [0.28, MeOH].

Step-2: Preparation of tert-butyl3-(5-(3-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(218b)

Compound (218b) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (1.607 g, 4.17 mmol) and(R)—N-((−)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(218a) (1.5 g, 3.79 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(3-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(218b) (1.96 g, 2.57 mmol, 67.8% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.62 (d,J=8.1 Hz, 1H), 7.58-7.32 (m, 9H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.9Hz, 1H), 5.39 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.37(s, 9H), 1.13 (s, 9H), 1.20-1.00 (m, 1H), 0.97-0.77 (m, 1H), 0.70-0.55(m, 1H), 0.40-0.27 (m, 2H), −0.01-−0.18 (m, 2H); MS (ES+) 763.5 (M+1),785.6 (M+Na); (ES−) 761.5 (M−1); Optical rotation: [α]_(D)=(−) 65.96[0.285, MeOH].

Step-3: Preparation of(+)-N-(3-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(218c)

To a stirred solution of tert-butyl3-(5-(3-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(218b) (1.014 g, 1.329 mmol) in ethanol (15 mL) was added conc. HCl(1.10 mL, 13.2 mmol) and heated at reflux for 1 h. The reaction mixturewas concentrated in vacuum to dryness and the residue obtained waspurified twice by flash column chromatography (silica gel 40 g, firstcolumn eluting with 0-50% CMA-80 in chloroform, second column elutingwith methanol in chloroform 0-30%) to obtain compound 218c (479 mgs,0.699 mmol, 52.6% yield) free base as a white solid. The free base wasdissolved in ethanol (5 mL) added conc. HCl (0.18 mL) and concentratedin vacuum to dryness to afford a white residue, which was dissolved inwater (5 mL) and concentrated in vacuum to dryness to afford(+)-N-(3-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(218c) (276 mg, 0.417 mmol, 31.39% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.39 (s, 3H), 8.42 (s,3H), 7.94 (d, J=8.4 Hz, 2H), 7.78-7.47 (m, 9H), 7.43 (t, J=8.0 Hz, 1H),7.21 (d, J=8.0 Hz, 1H), 4.18-4.08 (m, 2H), 2.60-2.40 (m, 2H), 1.23-1.01(m, 2H), 0.68 (s, 1H), 0.37 (dd, J=8.0, 4.1 Hz, 2H), 0.11-0.14 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.59; MS (ES+): 559.5 (M+1); IR (KBr)2233 cm⁻¹; Optical rotation: [α]_(D)=(+) 16.72 [0.335, MeOH]; Analysiscalculated for C₃₁H₂₉F₃N₆O.2HCl.3H₂O: C: 54.31; H: 5.44; N: 12.26; FoundC: 54.20; H: 5.44; N: 12.11.

Preparation of(+)-N-(3-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(219c) Step: 1 Preparation of(R)—N-((−)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(219a)

Compound (219a) was prepared from(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(214d) (2 g, 6.64 mmol), using procedure as reported in step-2 of scheme208 to afford(R)—N-((−)-1-(3-aminophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(219a) (1.939 g, 4.9 mmol, 74.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.78 (t, J=1.6 Hz, 1H), 7.72-7.61 (m, 2H), 7.50 (t,J=7.8 Hz, 1H), 6.94 (t, J=7.8 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 6.46 (dt,J=7.9, 1.2 Hz, 1H), 6.39 (ddd, J=8.0, 2.2, 0.9 Hz, 1H), 5.16 (s, 1H),5.05 (s, 2H), 2.73-2.36 (m, 2H), 1.13 (s, 9H), 1.25-1.05 (m, 1H),0.99-0.79 (m, 1H), 0.73-0.56 (m, 1H), 0.45-0.24 (m, 2H), 0.05-−0.19 (m,2H); MS (ES+) 396.4 (M+1) 418.4 (M+Na); (ES−) 394.6 (M−1) 430.4 (M+Cl);Optical rotation: [α]_(D)=(−) 117.6 [0.25, MeOH].

Step-2: Preparation of tert-butyl3-(5-(3-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(219b)

Compound (219b) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (1.286 g, 3.34 mmol) and(R)—N-((−)-1-(3-aminophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(219a) (1.2 g, 3.03 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(3-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(219b) (1.081 g, 1.417 mmol, 46.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.71 (d, J=7.5Hz, 1H), 7.66-7.32 (m, 10H), 7.28 (t, J=8.0 Hz, 1H), 7.11 (d, J=7.9 Hz,1H), 5.39 (s, 1H), 4.19 (d, J=6.1 Hz, 2H), 2.73-2.36 (m, 2H), 1.37 (s,9H), 1.13 (s, 9H), 1.12 (m, 1H), 1.00-0.80 (m, 1H), 0.70-0.55 (m, 1H),0.40-0.31 (m, 2H), −0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.58;MS (ES+) 785.6 (M+Na); (ES−) 761.5 (M−1); Optical rotation: [α]_(D)=(−)73.68 [0.285, MeOH].

Step-3: Preparation of(+)-N-(3-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(219c)

To a stirred solution of tert-butyl3-(5-(3-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(219b) (0.7 g, 0.918 mmol) in ethanol (12 mL) was added conc. HCl (0.76mL, 9.12 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was purifiedtwice by flash column chromatography (silica gel 25 g, first columneluting with 0-30% CMA-80 in chloroform, second column eluting withmethanol in chloroform 0-10%) to afford compound 219c (297 mgs, 0.532mmol, 57.9% yield) free base as a white solid. The free base (126 mgs,0.23 mmol) was dissolved in ethanol (5 mL) added conc. HCl (0.095 mL)and concentrated in vacuum to dryness to afford a white residue, whichwas dissolved in water (5 mL) and concentrated in vacuum to dryness toafford(+)-N-(3-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(219c) (130 mg, 0.192 mmol, 83.54% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.37 (s, 3H), 8.41 (s,3H), 7.91-7.84 (m, 2H), 7.76-7.48 (m, 9H), 7.43 (t, J=8.0 Hz, 1H), 7.21(d, J=7.9 Hz, 1H), 4.13 (bs, 2H), 2.6-0-2.40 (m, 2H), 1.19-0.99 (m, 2H),0.77-0.60 (m, 1H), 0.46-0.30 (m, 2H), 0.14-0.12 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.60; MS (ES+): 559.5 (M+1); IR (KBr) 2235 cm⁻¹;Optical rotation: [α]_(D)=(+) 7.59 [CH₃OH, 0.29]; Analysis calculatedfor C₃₁H₂₉F₃N₆O.2HCl.2.5H₂O: C: 55.03; H: 5.36; N: 12.42; Found C:55.07; H: 5.15; N: 12.30.

Preparation of(+)-N-(5-(1-amino-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(220f) Step-1: Preparation of 2-(3-cyclopropylpropanoyl)pyridine 1-oxide(220a)

To solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (59d) (2.98 g,17.01 mmol) in CH₂Cl₂ (120 mL) cooled to ˜0° C. was added3-chlorobenzoperoxoic acid (11.43 g, 51.0 mmol), stirred at ˜0° C. for 3h and allowed to warm to room temperature overnight. The reactionmixture was concentrated in vacuum and purified by flash columnchromatography [silica gel, eluting with hexanes/10% methanol in ethylacetate (1:0 to 1:1)] to afford 2-(3-cyclopropylpropanoyl)pyridine1-oxide (220a) (1.115 g, 5.83 mmol, 34.3% yield) as a light brown oil;¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (dt, J=6.4, 0.8 Hz, 1H), 7.62-7.51 (m,2H), 7.42 (td, J=7.7, 1.1 Hz, 1H), 3.13-3.06 (m, 2H), 1.48 (q, J=7.2 Hz,2H), 0.79-0.59 (m, 1H), 0.45-0.25 (m, 2H), 0.09-−0.07 (m, 2H); MS (ES+)214.2 (M+Na); (ES−) 190.2 (M−1).

Step-2: Preparation of 6-(3-cyclopropylpropanoyl)picolinonitrile (220b)

To a solution of 2-(3-cyclopropylpropanoyl)pyridine 1-oxide (220a)(1.026 g, 5.37 mmol) and trimethylsilanecarbonitrile (3.22 mL, 23.66mmol) in CH₂Cl₂ (25 mL) cooled to 0 OC was added dimethylcarbamicchloride (2.110 mL, 22.06 mmol) and stirred at room temperature for 86h. The reaction mixture was concentrated in vacuum and purified by flashcolumn chromatography [silica gel, eluting with hexanes/ethyl acetate(1:0 to 1:1)] to afford 6-(3-cyclopropylpropanoyl)picolinonitrile (220b)(117 mg, 0.584 mmol, 10.89% yield) as a yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.34-8.19 (m, 3H), 3.25 (t, J=7.3 Hz, 2H), 1.54 (q, J=7.2 Hz,2H), 0.87-0.60 (m, 1H), 0.50-0.30 (m, 2H), 0.11-0.01 (m, 2H); MS (ES+)223.2 (M+Na), (ES−) 199.1 (M−1).

Step-3: Preparation of(−)-N-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(220c)

Compound (220c) was prepared from6-(3-cyclopropylpropanoyl)picolinonitrile (220b) (1 g, 4.99 mmol) and(R)-2-methylpropane-2-sulfinamide (608 mg, 5.02 mmol) using procedure asreported in step-1 of scheme 208 to afford(−)-N-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(220c) (782 mg, 2.58 mmol, 51.6% 30 yield) as a yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.33-8.16 (m, 3H), 3.55-3.20 (m, 2H), 1.57-1.43 (m,2H), 1.26 (s, 9H), 0.85-0.63 (m, 1H), 0.45-0.27 (m, 2H), 0.08-−0.01 (m,2H); MS (ES+) 304.3, (M+1), 326.3 (M+Na); (ES−) 338.2 (M+Cl); OpticalRotation [α]_(D)=(−) 79.35 [0.31, MeOH].

Step-4: Preparation of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(220d)

Compound (220d) was prepared from(−)-N-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(220c) (0.695 g, 2.291 mmol), using procedure as reported in step-2 ofscheme 208 to afford(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(220d) (0.345 g, 0.832 mmol, 36.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.01-7.88 (m, 2H), 7.61 (dd, J=7.1, 2.2 Hz, 1H), 6.90(dd, J=11.3, 8.5 Hz, 1H), 6.66 (dd, J=8.8, 2.4 Hz, 1H), 6.49 (ddd,J=8.5, 4.2, 2.3 Hz, 1H), 5.56 (s, 1H), 5.12 (s, 2H), 2.75-2.30 (m, 2H),1.26-0.87 (m, 2H), 1.14 (s, 9H), 0.72-0.56 (m, 1H), 0.42-0.30 (m, 2H),0.06 to −0.14 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.02; MS (ES+):437.4 (M+Na); (ES−) 413.4 (M−1), 449.4 (M+Cl); Optical Rotation[α]_(D)=(−) 7.80 [0.205, MeOH].

Step-5: Preparation of tert-butyl3-(5-(5-((−)-1-(6-cyanopyridin-2-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(220e)

Compound (220e) was prepared using1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.34 g, 0.882 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(220d) (323 mg, 0.779 mmol) using procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((−)-1-(6-cyanopyridin-2-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(220e) (273 mg, 0.349 mmol, 44.8% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.05-7.91 (m, 2H), 7.67 (d, J=7.9 Hz,1H), 7.61-7.16 (m, 9H), 5.80 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.80-2.54(m, 2H), 1.38 (s, 9H), 1.13 (s, 9H), 1.10-0.85 (m, 2H), 0.75-0.55 (m,1H), 0.40-0.30 (m, 2H), 0.05 to −0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.62, −122.28; MS (ES+) 804.7 (M+Na); Optical Rotation[α]_(D) (−) 7.46 [0.295, MeOH].

Step-6: Preparation of(+)-N-(5-(1-amino-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(220f)

To a stirred solution of tert-butyl3-(5-(5-((−)-1-(6-cyanopyridin-2-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(220e) (144 mg, 0.184 mmol) in ethanol (15 mL) was added conc. HCl (0.15mL, 1.808 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was purifiedtwice by flash column chromatography (silica gel 25 g, first columneluting with 0-30% CMA-80 in chloroform, second column eluting withmethanol in chloroform 0-10%) to afford compound 220f (41 mg, 0.071mmol, 38.5% yield) free base as a white solid. The free base (41 mg,0.071 mmol) was dissolved in ethanol (10 mL) added conc. HCl (0.03 mL)and concentrated in vacuum to dryness to afford a white residue, whichwas dissolved in water (2 mL) and concentrated in vacuum to dryness toafford(+)-N-(5-(1-amino-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(220f) (50 mg, 0.071 mmol, 38.57% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.12 (s, 3H), 8.32 (s,3H), 8.14 (s, 1H), 7.89-7.16 (m, 10H), 4.13 (s, 2H), 1.32-1.10 (m, 1H),1.00-0.75 (m, 1H), 0.75-0.57 (m, 1H), 0.42-0.32 (m, 2H), 0.08 to −0.08(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.64, −119.69; MS (ES+): 600.5(M+Na); Optical Rotation [α]_(D)=(+) 57.39 [0.23, MeOH]; Analysiscalculated for C₃₀H₂₇F₄N₇O.2HCl.3H₂O: C: 51.14; H: 5.01; N: 13.92; Cl:10.06; Found: C: 51.40; H: 4.90; N: 13.58; Cl: 10.00.

Preparation of(+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)-3-cyclopropylpropyl)picolinamide(221i) Step: 1 Preparation of1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one (221b)

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanone (221a) (35 g,171 mmol) in methanol (400 mL) at 0° C. was addedcyclopropanecarboxaldehyde (21 mL, 281 mmol) followed by potassiumhydroxide (1 M aqueous solution, 35 mL, 35 mmol). The reaction mixtureallowed to attain room temperature and stirred for 13 h. The reactionwas acidified with 1 N HCl (40 mL) to pH-6 and concentrated in vacuummaintaining bath temperature below 35° C. The residue was dissolved inethyl acetate (700 mL) washed with water (300 mL), dried, filtered andconcentrated in vacuum to furnish crude1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one (221b) (40.45 g) asa colorless liquid which was used as such for next step.

Step 2: Preparation of 1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one(221c)

To a stirred solution of crude1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one (221b) (40.45 g)from above step in acetonitrile (300 mL) was added tri-n-butyltinhydride (88 mL, 319 mmol) and heated at reflux for 13 h. The reactionmixture was cooled to room temperature and the layers separated. Thelower layer was extracted with acetonitrile (150 mL) and bothacetonitrile layers were combined and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica geleluting with ethyl acetate in hexanes 0 to 100%) to afford1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one (221c) (11.57 g, 45.5mmol, 28.5% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.94(dd, J=2.6, 0.8 Hz, 1H), 8.22 (dd, J=8.3, 2.5 Hz, 1H), 7.83 (dd, J=8.3,0.8 Hz, 1H), 3.14 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1 Hz, 2H), 0.84-0.66(m, 1H), 0.44-0.25 (m, 2H), 0.15-−0.17 (m, 2H); MS (ES−) 252.2 (M−1).

Step-3: Preparation of 5-(3-cyclopropylpropanoyl)picolinonitrile (221d)and 5-(3-cyclopropylpropanoyl)picolinamide (221e)

A mixture of 1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one (221c)(11.23 g, 44.2 mmol) and cyanocopper (7.92 g, 88 mmol) in DMF (150 mL)was stirred at 110° C. for 45 h. The reaction mixture was cooled to roomtemperature, diluted with water (200 mL) and ethyl acetate (500 mL). Themixture was filtered and aqueous layer was separated, extracted withethyl acetate. The organic layers were combined washed with saturatedaqueous NaHCO₃ (150 mL), brine (150 mL), dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel eluting with ethyl acetate in hexanes(1:0 to 4:1 to 1:1)] to furnish:

-   -   1. 5-(3-cyclopropylpropanoyl)picolinonitrile (221d) (3.642 g,        18.19 mmol, 41.2%) as a yellow oil): ¹H NMR (300 MHz, DMSO-d₆) δ        9.23 (dd, J=2.2, 0.9 Hz, 1H), 8.53 (dd, J=8.1, 2.2 Hz, 1H), 8.22        (dd, J=8.1, 0.9 Hz, 1H), 3.20 (t, J=7.2 Hz, 2H), 1.53 (q, J=7.1        Hz, 2H), 0.91-0.61 (m, 1H), 0.53-0.23 (m, 2H), 0.15-0.00 (m,        2H); MS (ES+) 201.2 (M+1); (ES−) 199.2 (M−1).    -   2. 5-(3-cyclopropylpropanoyl)picolinamide (221e) (481 mg, 2.204        mmol, 4.99% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ        9.12 (dd, J=2.2, 0.9 Hz, 1H), 8.48 (dd, J=8.2, 2.2 Hz, 1H), 8.27        (s, 1H), 8.15 (dd, J=8.2, 0.8 Hz, 1H), 7.84 (s, 1H), 3.20 (t,        J=7.2 Hz, 2H), 1.54 (q, J=7.1 Hz, 2H), 0.87-0.63 (m, 1H),        0.46-0.32 (m, 2H), 0.13-0.03 (m, 2H); MS (ES+) 219.2 (M+1);        241.2 (M+Na).

Step-4: Preparation of(R)-(−)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)picolinamide(221f)

Compound 212f was prepared from 5-(3-cyclopropylpropanoyl)picolinamide(221e) (458 mg, 2.098 mmol) and (R)-2-methylpropane-2-sulfinamide (331mg, 2.73 mmol), using procedure as reported in step-1 of scheme 208 toafford(R)-(−)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)picolinamide(221f) (393 mg, 1.223 mmol, 58.3% yield) as a light yellow syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.20 (s, 1H),8.11 (d, J=8.2 Hz, 1H), 7.80 (s, 1H), 3.52-3.27 (m, 2H), 1.59-1.37 (m,2H), 1.25 (s, 9H), 0.87-0.62 (m, 1H), 0.50-0.28 (m, 2H), 0.12-−0.00 (m,2H); MS (ES+) 344.3 (M+Na) Optical rotation: [α]_(D)=(+) 7.27 [0.11,MeOH].

Step-5: Preparation of5-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)picolinamide(221g)

Compound (221g) was prepared from(R)-(−)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)picolinamide(221f) (373 mg, 1.16 mmol), using procedure as reported in step-2 ofscheme 208 to afford5-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)picolinamide(221g) (287 mg, 0.663 mmol, 57.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.53-8.49 (m, 1H), 8.08 (s, 1H), 8.00-7.87 (m, 2H), 7.62(s, 1H), 6.92 (dd, J=11.2, 8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.3 Hz, 1H),6.56-6.46 (m, 1H), 5.42 (s, 1H), 5.12 (s, 2H), 2.62-2.38 (m, 2H),1.30-0.77 (m, 2H), 1.13 (s, 9H), 0.75-0.55 (m, 1H), 0.42-0.30 (d, J=8.0Hz, 2H), 0.02 to −0.15 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.37; MS(ES+) 455.4 (M+Na); Optical rotation: [α]_(D)=(−) 78.75 [0.16, MeOH].

Step-6: Preparation of tert-butyl3-(5-(5-((−)-1-(6-carbamoylpyridin-3-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(221h)

Compound (221h) was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (290 mg, 0.751 mmol) and5-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)picolinamide(221g) (260 mg, 0.601 mmol) using the procedure as reported in step-3 ofscheme 208 to afford tert-butyl3-(5-(5-((−)-1-(6-carbamoylpyridin-3-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(221h) (115 mg, 0.144 mmol, 19.17% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.09 (d,J=2.7 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.92-7.84 (m, 1H), 7.69-7.20 (m,10H), 5.71 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s,9H), 1.13 (s, 9H), 1.15-1.13 (m, 1H), 1.00-0.80 (m, 1H), 0.70-0.55 (m,1H), 0.40-0.27 (m, 2H), 0.00 to −0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.81, −122.88; MS (ES+) 822.5 (M+Na), (ES−) 798.5 (M−1);Optical rotation: [α]_(D)=(−) 44.71 [0.085, MeOH].

Step-7: Preparation of(+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)-3-cyclopropylpropyl)picolinamide(221i)

To a stirred solution of tert-butyl3-(5-(5-((−)-1-(6-carbamoylpyridin-3-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(221h) (100 mg, 0.125 mmol) in ethanol (15 mL) was added conc. HCl (0.11mL, 1.325 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness and the residue obtained was suspendedin ethanol (2 mL) and triturated with t-butyl methyl ether (20 mL). Thesolid obtained was collected by filtration and washed with ether. Thisresidue was dissolved in water (1 mL) and lyophilized to afford of(+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)-3-cyclopropylpropyl)picolinamide(221i) (42 mg, 0.059 mmol, 47.38% yield) hydrochloride as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H), 9.60 (s, 3H), 8.68-8.62 (m,1H), 8.43 (s, 3H), 8.18 (d, J=2.9 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.94(dd, J=8.4, 2.4 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.68 (s,1H), 7.61 (dt, J=7.3, 1.7 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (dd, J=8.5,3.7 Hz, 2H), 4.11 (q, J=5.8 Hz, 2H), 2.64-2.53 (m, 2H), 1.27-0.99 (m,2H), 0.69 (m, 1H), 0.43-0.32 (m, 2H), 0.00 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.83, −120.35; MS (ES+) 618.462 (M+Na), (ES−) 594.458(M−1); Optical rotation: [α]_(D)=(+) 7.55 [0.265, MeOH]; Analysiscalculated for C₃₀H₂₉F₄N₇O₂.2HCl.2.25H₂O: C, 50.82; H, 5.05; Cl, 10.00;N, 13.83; Found: C, 50.87; H, 5.41; Cl, 10.23; N, 13.44.

Preparation of(−)-1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222j) Step-1: Preparation of(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (222a)

To a stirred solution of benzaldehyde (259 mL, 2541 mmol) intetrahydrofuran (2500 mL) was added(R)-2,4,6-triisopropylbenzenesulfinamide (280 g, 2310 mmol),tetraisopropoxytitanium (1382 mL, 4620 mmol) and stirred at roomtemperature for 36 h. The reaction mixture was diluted with 1 L of brinewith vigorous stirring, followed by ethyl acetate (6 L) and stirred for4 h. The reaction mixture was filtered washed with ethyl acetate (6×2L). The organic layers were combined washed with a solution of sodiummetabisulfite (329 mL, 1733 mmol), water (462 mL) dried over MgSO₄,filtered, evaporated to dryness. The crude residue was purified by flashcolumn chromatography (silica gel 1.5 kg, eluting with 20% ethyl acetatein hexane) to furnish(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (472.51 g,2257 mmol, 98% yield) as a pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.57 (s, 1H), 8.03-7.89 (m, 2H), 7.70-7.48 (m, 3H), 1.19 (s, 9H); MS(ES+) 232.18 (M+Na); Optical rotation: [α]_(D)=(−) 112.11 [4.155,CHCl₃].

Step-2: Preparation of(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) and(R)—N—((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222c) Batch-1:

To a solution of (R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide(222a) (475 g, 2269 mmol) in toluene (4 L) cooled to −11° C. was addeddropwise freshly prepared Grignard reagent(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(4.75 L, 3563 mmol) over a period of 70 minutes, maintaining internalbetween temp (−11.1 to −10° C.). Reaction mixture was stirred at thesame temperature until complete (check TLC for reaction completion).

Reaction was quenched with 1N KHSO₄ at −10° C. The reaction was warmedto room temperature over a 30 mins period and organic layer wasseparated. The aqueous layer was extracted with ethyl acetate (2×2 L).The organic layers were combined washed water (2×2 L), brine (3.5 L),dried filtered and concentrated in vacuum to afford crude oil containingmixture of diastereoisomers of(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) and(R)—N—((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222c) [(de=72/28) 727 g, 2269 mmol]. To crude in a 22 L flash was addedIPA (2000 mL) and heated at reflux with stirring (30 mins to completelysolubilize). The reaction mixture was cooled to 27° C. over a period of5 h with gentle stirring. The solid obtained was collected by filtrationwashed with IPA (5×100 mL), air dried for 24 h to furnish(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (351 g, 48.3% yield, de=94.63%.) as a white crystalline solid.

Batch-2:

The above procedure was repeated using(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (0.500 kg,2.389 mol) to furnish(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (329 g, 43% yield, de=93.58%.) as a white crystalline solid.

Batch-3:

The above procedure was repeated using(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (409 g, 1953mmol) to furnish(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (264 g, 42% yield, de=94.33%.) as a white crystalline solid.

Second Crystallization:

The above three batches were combined In a 22 L wide mouth rotaryevaporator flash fitted with a mechanical stirrer containing mixture ofdiastereoisomers of (222b) and (222c) (batch-1, 351 g, 48.3% yield,de=94.63%), (batch-2, 329 g, 43% yield, de=93.58%) and (batch-3, 264 g,42% yield, de=94.33%) was added IPA (4000 mL) and heated at reflux withstirring (50 mins to completely solubilize). The reaction mixture wascooled to room temperature overnight with gentle stirring (13° C.). Thesolid crystallized after about 1 h of cooling and stirring was continuedovernight. The solid obtained was collected by filtration washed withIPA (1×100 mL and 2×200 mL), dried in high vacuum for 24 h to furnish(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (872 g, 92% yield, de=99.2852%.) as a white crystalline solid; ¹HNMR (300 MHz, DMSO-d₆) δ 7.40-7.26 (m, 4H), 7.25-7.15 (m, 1H), 6.90 (dd,J=11.5, 8.3 Hz, 1H), 6.75 (dd, J=8.9, 2.2 Hz, 1H), 6.57 (ddd, J=8.4,4.4, 2.2 Hz, 1H), 5.77 (d, J=5.4 Hz, 1H), 5.33 (d, J=5.3 Hz, 1H), 5.11(s, 2H), 1.13 (s, 9H); ¹⁹F NMR (282 MHz, DMSO) δ −137.36; ¹³C NMR (75MHz, DMSO) δ 151.32, 148.19, 143.13, 139.74, 139.70, 128.22, 127.63,126.93, 115.04, 114.98, 114.91, 114.82, 114.60, 114.35, 61.88, 55.42,22.77; Optical rotation: [α]_(D)=(−) 70.70 (MeOH, 1.065); Analysiscalculated for C₁₇H₂₁FN₂OS: C, 63.72; H, 6.61; N, 8.74; Found: C, 63.74;H, 6.74; N, 8.74.

Data for(R)—N—((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222c); ¹H NMR (300 MHz, DMSO-d₆) δ 7.41-7.36 (m, 2H), 7.36-7.27 (m,2H), 7.26-7.18 (m, 1H), 6.89 (dd, J=11.5, 8.3 Hz, 1H), 6.71 (dd, J=8.9,2.2 Hz, 1H), 6.51 (ddd, J=8.4, 4.5, 2.2 Hz, 1H), 5.82 (d, J=5.5 Hz, 1H),5.32 (d, J=5.5 Hz, 1H), 5.09 (s, 2H, 1H D₂O exchangeable), 1.14 (s, 9H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.32; MS (ES+) 321.3 (M+1), 343.3(M+Na), 663.5 (2M+Na); MS (ES−) 319.3 (M−1). Optical rotation:[α]_(D)=(−) 73.21 (MeOH, 2.505).

Step-3: Preparation of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline(222d)

To a mechanically stirred slurry of(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (99.13 g, 309 mmol) in MTBE (600 mL) was added 4M HCl (dioxane)(162 mL, 650 mmol) and stirred at room temperature for 11 h. Solidstarts forming as soon as HCl addition is started. TLC analysis showsunreacted starting material, additional 4M HCl (dioxane) (162 mL, 650mmol) was added and stirred at room temperature for 16 h. Excessmethanol was evaporated, mixture basified with 3N NaOH (455 mL) andcompound was extracted with ethyl acetate (2×750 mL). The combinedorganic layers were dried over anhydrous MgSO₄, filtered, evaporated todryness. The solid was triturated with hexanes, stirred for 1 h andsolid obtained was collected by filtration to afford(+)-5-(amino(phenyl)methyl)-2-fluoroaniline (222d) (38.0 g, 57% yield)as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.33 (m, 2H),7.27 (ddd, J=7.6, 6.6, 1.2 Hz, 2H), 7.21-7.13 (m, 1H), 6.86 (dd, J=11.5,8.3 Hz, 1H), 6.77 (dd, J=9.0, 2.2 Hz, 1H), 6.54 (ddd, J=8.3, 4.4, 2.2Hz, 1H), 5.03 (s, 2H, D₂O exchangeable), 4.96 (s, 1H), 2.71 (s, 2H, D₂Oexchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −138.12; MS (ES+) 217.2(M+1); 215.1 (M−1); Optical rotation: [α]_(D)=(+) 1.47 (0.545, MeOH).

Step-4: Preparation of(−)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(222e) and(−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f)

To a stirred solution of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline(222d) (5.312 g, 24.56 mmol) in MeOH (80 mL) was addedcyclopropanecarboxaldehyde (1.944 mL, 25.8 mmol) at 0° C. for a periodof 10 min and stirred for 30 mins. To this sodium borohydride (1.859 g,49.1 mmol) was added in multiple portions and stirred for 1 h at 0° C.Excess solvent was evaporated and residue was treated with water (100mL), and extracted with ethyl acetate (2×100 mL). The organic layerswere combined dried over anhydrous MgSO₄, filtered and evaporated todryness. The residue was purified by flash column chromatography (silicagel 80 g, eluting with 0-100% ethyl acetate in hexanes) to furnish

-   -   1.        (−)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (222e) (0.663 g, 8% yield) as an yellow oil as a yellow oil; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.44-7.35 (m, 2H), 7.30-7.21 (m, 2H),        7.19-7.08 (m, 1H), 6.96-6.75 (m, 2H), 6.55 (ddd, J=8.3, 4.6, 2.0        Hz, 1H), 5.26 (td, J=6.0, 2.3 Hz, 1H, D₂O exchangeable), 4.71        (s, 1H), 2.93 (t, J=6.2 Hz, 2H), 2.27 (d, J=7.1 Hz, 3H, 1H, D₂O        exchangeable), 1.09-0.84 (m, 2H), 0.39 (m, 4H), 0.25-0.15 (m,        2H), 0.09-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.56;        MS (ES+) 325.4 (M+1); Optical rotation: [α]_(D)=(−) 6.67 [0.27,        methanol]    -   2.        (−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (222f) (4.84 g, 73% yield) as a yellow oil; ¹H NMR (300 MHz,        DMSO-d₆) δ 7.42-7.34 (m, 2H), 7.32-7.23 (m, 2H), 7.22-7.11 (m,        1H), 6.92-6.78 (m, 2H), 6.55 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.04        (s, 2H, D₂O exchangeable), 4.67 (s, 1H), 2.25 (td, J=9.6, 5.3        Hz, 3H; 1H D₂O exchangeable), 1.04-0.80 (m, 1H), 0.50-0.28 (m,        2H), 0.11-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.92; MS        (ES−) 269.3 (M−1); Optical rotation: [α]_(D)=(−) 12.24 [1.275,        CHCl₃]; Chiral purity checked by performing chiral HPLC using        chiral AD-H column, 1 mL/min, Solvent: 95% Hexane, 5%        isopropanol, UV=260 nM, 25° C. (>99.99 ee).

Step-5: Preparation of5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(222h)

To a suspension of 5-amino-2-fluorobenzonitrile (222g) (25 g, 184 mmol)in 12N HCl (55.1 mL, 661 mmol) was added a solution of sodium nitrite(15.21 g, 220 mmol) in water (75 mL) at 0° C. After stirring for 1 h, tothe mixture was added tin(II) chloride dihydrate (83 g, 367 mmol)pre-dissolved in 12N HCl (55.1 mL, 661 mmol) at such a rate that thetemperature was not allowed to go above 5 OC. After stirring for 2 h, asolution of 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (10b) (37.9g, 184 mmol) in ethanol (305 mL) was added and heated at 60° C. for 21h. The reaction mixture was cooled to room temperature and concentratedin vacuum to remove ethanol. The aqueous was basified with saturatedNaHCO₃ and extracted with ethyl acetate (3×500 mL). The organic layerswere combined dried over MgSO₄, filtered, and concentrated to dryness.The residue obtained was purified by flash column chromatography [silicagel 750 g, eluting with ethyl acetate in hexanes, from 0-100%] tofurnish5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(222h) (11.5 g, 35.8 mmol, 19.49% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.30 (dd, J=5.7, 2.7 Hz, 1H), 8.06-7.98 (m, 1H),7.82-7.70 (m, 2H), 7.34 (s, 1H), 6.59 (dd, J=3.5, 1.8 Hz, 1H), 6.49 (d,J=3.5 Hz, 1H); MS (ES⁺): MS (ES+) 665.3 (2M+Na).

Step-6: Preparation of1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (222i)

To a stirred solution of5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile(222h) (11.1 g, 34.6 mmol) in acetone (200 mL) was added a solution ofpotassium permanganate (38.2 g, 242 mmol) in water (100 mL) drop-wiseover a period of 30 min. This mixture was heated at 60° C. for 2 h,cooled to room temperature and quenched with 2-propanol (200 mL). Thereaction mixture was stirred at room temperature overnight and filteredthrough Celite washed with acetone/water mixture (2×50 mL), methanol(2×75 mL). The organic solvent was removed by evaporation under reducedpressure. The reaction mixture was basified with 1N NaOH, washed withether (2×150 mL). Aqueous layer was poured on to crushed ice, acidifiedvery carefully with aq. 1N HCl under constant stirring. The solidobtained was collected by filtration, washed with hexanes (2×50 mL),dried over P₂O₅ to furnish1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (222i) (8.384 g, 81% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 14.03 (s, 1H, D₂O exchangeable), 8.36 (dd, J=5.7, 2.7 Hz,1H), 8.07 (ddd, J=9.0, 4.7, 2.7 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.57(s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.77, −106.91; MS (ES⁺): MS(ES+) 300.2 (M+1); MS (ES+) 298.2 (M−1), 597.3 (2M−1).

Step-7: Preparation of(−)-1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222j)

Compound 222j was prepared from1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (222i) (1.461 g, 4.88 mmol) and(−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f)(1.1 g, 4.07 mmol) using the procedure reported in scheme 208 step-3gave(−)-1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222j) (2.239 g, 100% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.50 (s, 1H, D₂O exchangeable), 8.28 (dd, J=5.7, 2.7 Hz, 1H), 8.00(ddd, J=9.2, 4.7, 2.8 Hz, 1H), 7.76-7.65 (m, 2H), 7.55 (dd, J=7.5, 2.1Hz, 1H), 7.42-7.30 (m, 4H), 7.30-7.23 (m, 1H), 7.22-7.14 (m, 2H), 4.84(s, 1H), 2.44 (s, 1H), 2.34-2.22 (m, 2H), 1.02-0.84 (m, 1H), 0.47-0.28(m, 2H), 0.08-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82,−107.26, −123.06; MS (ES+): MS (ES−) 550.04 (M−1); Optical rotation:[α]_(D)=(−) 5.6 [0.25, CH₃OH].

Step-8: Preparation of(−)-1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222k)

To a stirred solution of potassium tert-butoxide (1.481 g, 13.20 mmol)and acetohydroxamic acid (0.991 g, 13.20 mmol) in DMF (20 mL) stirredfor 35 min at room temperature was added(−)-1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222j) (2.206 g, 4 mmol) in DMF (20 mL). The mixture was stirred at roomtemperature for 16 h. The mixture was poured into a separatory funnelcontaining 100 mL of aqueous ammonium chloride and 100 mL of EtOAc.Aqueous layer was separated and extracted with EtOAc (100 mL). Theorganic layers were combined dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue was purified by flash columnchromatography (First column: silica gel 40 g, eluting with 0-100% ethylacetate in hexanes; second column: silica gel 40 g, eluting with 0-50%CMA80 in chloroform; third column: silica gel 40 g) to furnish(−)-1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(222k) (0.221 g, 10% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.49 (s, 1H, D₂O exchangeable), 8.07 (d, J=2.1 Hz, 1H), 7.71-7.51 (m,4H), 7.41-7.35 (m, 2H), 7.34-7.24 (m, 3H), 7.22-7.13 (m, 2H), 6.59 (s,2H, D₂O exchangeable), 4.82 (s, 1H), 2.42 (s, 1H), 2.26 (d, J=6.0 Hz,2H), 0.89 (td, J=7.4, 3.8 Hz, 1H), 0.45-0.27 (m, 2H), 0.03 (dt, J=5.0,2.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.59, −123.45; MS (ES⁺): MS(ES+) 565.5 (M+1); Optical rotation: [α]_(D)=(−) 8.3 [0.265, CH₃OH].

Preparation of1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(223f) Step-1: Preparation of 5-(amino(phenyl)methyl)-2-fluoroaniline(223b)

Compound(R)—N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(223a) was obtained from the mother liquor from crystallization ofmixture of diastereoisomers of(R)—N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) and(R)—N—((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222c) in scheme-222. Compound 223b was prepared from(R)—N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(223a) (27.8 g, 87 mmol) using procedure reported in step-3 ofscheme-222 to furnish 5-(amino(phenyl)methyl)-2-fluoroaniline (223b) (14g, 75%) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.32(m, 2H), 7.27 (ddd, J=7.6, 6.7, 1.2 Hz, 2H), 7.21-7.11 (m, 1H), 6.86(dd, J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=9.0, 2.2 Hz, 1H), 6.54 (ddd,J=8.3, 4.5, 2.2 Hz, 1H), 5.00 (s, 2H), 4.93 (s, 1H), 2.13 (s, 2H); ¹⁹FNMR (282 MHz, DMSO) δ −138.30; MS (ES) 215.1 (M−1).

Step-2: Preparation ofN-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(223c) and 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(223d)

Compounds 223c and 223d was prepared from5-(amino(phenyl)methyl)-2-fluoroaniline (223b) (1.081 g, 5.00 mmol)according to procedure reported in step-4 of scheme-222 to furnish:

-   -   1.        N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (223c) (0.194 g, 0.598 mmol, 11.96% yield) as a colorless oil;        ¹H NMR (300 MHz, DMSO-d₆) δ 7.44-7.35 (m, 2H), 7.30-7.21 (m,        2H), 7.19-7.11 (m, 1H), 6.94-6.79 (m, 2H), 6.56 (ddd, J=8.2,        4.6, 2.1 Hz, 1H), 5.29 (td, J=5.9, 2.3 Hz, 1H), 4.72 (s, 1H),        2.94 (t, J=6.2 Hz, 2H), 2.38-2.20 (m, 3H), 1.10-0.97 (m, 1H),        0.91 (m, 1H), 0.40 (m, 4H), 0.21 (m, 2H), 0.03 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO) δ −137.78; MS (ES+) 325.3 (M+1); (ES−) 323.2        (M−1).    -   2. 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (223d) (0.795 g, 2.94 mmol, 58.8% yield) as a colorless oil; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.40-7.33 (m, 2H), 7.27 (tt, J=6.6, 0.9        Hz, 2H), 7.20-7.12 (m, 1H), 6.90-6.78 (m, 2H), 6.54 (ddd, J=8.3,        4.5, 2.1 Hz, 1H), 5.04 (s, 2H), 4.67 (s, 1H), 2.34-2.22 (m, 3H),        0.91 (m, 1H), 0.44-0.30 (m, 2H), 0.09-0.00 (m, 2H); ¹⁹F NMR (282        MHz, DMSO) δ −137.95; MS (ES+) 271.2 (M+1).

Step-3: Preparation of1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (223e)

Compound 223 e was prepared from1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (222h) (2 g, 6.68 mmol) using procedure reported in step-8 ofscheme-222 to furnish1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (223e) (1.823 g, 87% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.03 (d, J=2.1 Hz, 1H), 7.73 (dd, J=8.8, 2.2 Hz, 1H),7.63-7.51 (m, 2H), 6.57 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.63; MS (ES⁺): MS (ES+) 313.2 (M+1), MS (ES−) 311.1 (M−1),623.3 (2M−1).

Step-4: Preparation of1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(223f)

Compound 223f was prepared from1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (223e) (0.577 g, 1.849 mmol) and5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223d) (0.5g, 1.849 mmol) according to procedure reported in step-3 of scheme-208to furnish1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(223f) (0.171 g, 16% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.79 (s, 1H), 8.37 (t, J=2.2 Hz, 1H), 8.03-7.80 (m, 4H), 7.72-7.42(m, 7H), 6.88 (s, 2H), 5.12 (d, J=1.8 Hz, 1H), 2.73 (m, 1H), 2.62-2.50(m, 2H), 1.18 (m, 1H), 0.66 (m, 2H), 0.39-0.27 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.53 (d, J=2.4 Hz), −123.40; MS (ES⁺): MS (ES+) 565.4(M+1).

Preparation of1-(3-amino-1H-indazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224b) Step-1: Preparation of1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224a)

Compound 224a was prepared from1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (222h) (1.217 g, 4.07 mmol) and5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223d) (1.1g, 4.07 mmol) as reported in step-3 of scheme-208 to furnish1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224a) (1.38 g, 2.502 mmol, 61.5% yield) as a white solid which was usedsuch in the next step; MS (ES+) 552.4 (M+1); MS (ES−) 550.3 (M−1).

Step-2: Preparation of1-(3-amino-1H-indazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224b)

To a stirred solution of1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224a) (0.7 g, 1.269 mmol) in n-butanol (20 mL) was added hydrazinehydrate (1.539 mL, 31.7 mmol) and heated at refluxed overnight. Reactionmixture was cooled to room temperature and evaporated in vacuum todryness. The residue obtained was purified by flash columnchromatography [silica gel 24 g, eluting with CMA80 in chloroform,0-100%] to afford1-(3-amino-1H-indazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224b) (0.197 g, 27% yield) as a light yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.69 (s, 1H), 10.44 (s, 1H), 7.90 (t, J=1.4 Hz, 1H),7.65-7.52 (m, 2H), 7.41-7.34 (m, 2H), 7.33-7.23 (m, 5H), 7.22-7.12 (m,2H), 5.54 (s, 2H), 4.81 (s, 1H), 2.43 (s, 1H), 2.25 (m, 2H), 0.97-0.80(m, 1H), 0.41-0.30 (m, 2H), 0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.62, −123.79; MS (ES⁺): MS (ES+) 564.4 (M+1); MS (ES−) 562.3 (M−1).

Preparation of(−)-N-(5-(1-amino-1-(3-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(225a)

To a stirred solution of tert-butyl3-(5-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(214f) (7.268 g, 9.31 mmol) in ethanol (70 mL) was added conc. HCl (7.80mL, 94 mmol) and heated at reflux for 1 h. The reaction mixture wasconcentrated in vacuum to dryness to obtain white solid (7.173g). Thewhite solid was purified by flash column chromatography (silica gel, 24g eluting with CMA 80 in chloroform 0 to 100%) to afford(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(214g) contaminated with NH₄C₁. This was repurified by flash columnchromatography (silica gel, 24 g eluting with methanol in chloroform 0to 50%) to afford 214g (4.567 g) free base as a white solid.

The free base of (214g) (4.45 g) was dissolved in methanol (150 mL) andadded 4 N HCl (aq. 8.0 mL) followed by concentration in vacuum todryness to furnish (214g) (4.622 g) white solid as a HCl saltcontaminated with,(−)-N-(5-(1-amino-1-(3-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(225a) due to use of dilute HCl; The solid was purified by flash columnchromatography (silica gel, 120 g eluting with CMA 80 in chloroform 0 to100%) to furnish (214g) (3.8 g) freebase followed by (225a) (150 mg,0.252 mmol, 3.64% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.52 (s, 1H), 8.05-7.84 (m, 2H), 7.66 (dt, J=7.7, 1.3 Hz, 1H), 7.57 (d,J=5.3 Hz, 2H), 7.49 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 2H), 7.36-7.22 (m,3H), 7.18 (d, J=9.6 Hz, 1H), 3.78 (s, 2H), 2.30-2.17 (m, 6H), 1.02 (m,2H), 0.64 (m, 1H), 0.43-0.29 (m, 2H), −0.04-−0.12 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.72, −124.42; MS (ES+) 595.5 (M+1), 617.5 (M+Na),(ES−) 593.4 (M−1); Analysis calculated for C₃₁H₃₀F₄N₆₀₂.H₂O: C, 61.23;H, 5.22; N, 13.82; Found: C, 61.29; H, 5.40; N, 13.82; Optical rotation:[c]d=(−) 0.54 [1.15, methanol].

Preparation of1-(4-aminoquinazolin-6-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224b)

To a stirred solution of1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224a) (0.7 g, 1.269 mmol) in N,N-dimethyl acetamide (20 mL) was addedformimidamide acetate (1.321 g, 12.69 mmol) and heated at refluxovernight. Reaction mixture was cooled to room temperature, diluted withwater (50 mL) and extracted with ethyl acetate (2×50 mL). Combinedorganics were dried over anhydrous MgSO₄, filtered and evaporated todryness. The residue obtained was purified by flash columnchromatography [First column: silica gel 24 g, eluting with CMA80 inchloroform, 0-100%; second column: silica gel 24 g, eluting with ethylacetate/methanol (9:1) in hexanes from 0-100%] to furnish1-(4-aminoquinazolin-6-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(224b) (0.113 g, 15% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.52 (s, 1H, D₂O exchangeable), 8.47 (d, J=5.6 Hz, 2H), 7.97(s, 2H, D₂O exchangeable), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.73 (d, J=9.2Hz, 2H), 7.57 (dd, J=7.5, 2.2 Hz, 1H), 7.38 (dt, J=6.5, 1.4 Hz, 2H),7.35-7.23 (m, 3H), 7.22-7.13 (m, 2H), 4.82 (s, 1H), 2.43 (s, 1H), 2.25(m, 2H), 0.88 (m, 1H), 0.45-0.25 (m, 2H), 0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.76, −123.39; MS (ES+) 576.4 (M+1); MS (ES−) 574.4(M−1).

Preparation of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) Step-1: Preparation of1-(3-cyanophenyl)-N-(5-((−)-((R)-1,1-dimethylethylsulfinamido)-(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227a)

To a solution of(−)-N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(222b) (0.872 kg, 2.72 mol) in DMF (10 mL) was added1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(0.765 kg, 2.72 mol), N-ethyl-N-isopropylpropan-2-amine (2.37 L, 13.61mol) and bromo-tris-pyrrolidino phosphoniumhexa-fluorophosphate (PyBrOP,1.4 kg, 2.99 mol) and stirred at room temperature for 24 h. Additional(9i) (153 g, 0.54 mol), N-ethyl-N-isopropylpropan-2-amine (470 mL) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP, 280 g),DMF (500 mL) was added and stirred at room temperature for 24 h.Additional (9i) (77 g, 0.274 mol), N-ethyl-N-isopropylpropan-2-amine(470 mL) and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 140 g), DMF (500 mL) and stirred at room temperature for 24 h.After 72 h stirring at room temperature the reaction was diluted withethyl acetate (8 L), washed with water (14 L), brine, dried, filtered,and evaporated to dryness to afford 1-(3-cyanophenyl)-N-(5-((−)-((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227a) (3108.6 g) as an off white solid, which was pure enough to betaken to next step. An analytical sample was prepared dissolving (1.6gm) of crude in isopropanol (24 mL) by heating. The mixture was cooledto room temperature overnight with stirring and solid obtained wascollected by filtration washed with isopropanol and dried under vacuumovernight to furnish 0.6 gms compound 227a as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.15-8.08 (m, 1H), 7.99 (dt, J=7.8, 1.3Hz, 1H), 7.92-7.85 (m, 1H), 7.76-7.68 (m, 2H), 7.51 (dd, J=6.9, 2.2 Hz,1H), 7.41-7.18 (m, 7H), 6.08 (d, J=6.2 Hz, 1H), 5.53 (d, J=6.1 Hz, 1H),1.12 (s, 9H); ¹³C NMR (75 MHz, DMSO) δ 156.11, 152.88, 142.57, 140.13,140.09, 139.81, 138.41, 132.99, 130.48, 130.35, 129.27, 127.66, 127.18,126.71, 126.61, 125.31, 123.85, 123.68, 117.76, 115.93, 115.66, 111.83,108.09, 61.71, 55.55, 22.75; ¹⁹F NMR (282 MHz, DMSO) δ −60.99, −122.46;MS (ES+) 584.1 (M+1); (ES−) 582.2 (M−1); Optical rotation: [α]_(D)=(−)49.20 (1.065, Methanol); Analysis calculated for C₂₉H₂₅F₄N₅O₂S: C,59.68; H, 4.32; N, 12.00; Found: C, 59.37; H, 4.61; N, 11.96.

Step-2: Preparation of(−)-N-(5-(amino(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (227b)

To a solution of1-(3-cyanophenyl)-N-(5-((−)-((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227a) (550 g, 942 mmol) in MeOH (6 L) was added drop-wise at roomtemperature hydrogen chloride (0.415 L, 1659 mmol, 4 N in 1,4-dioxane)over a period of 30 min and stirred for 30 mins. Additional hydrogenchloride (70 mL, 4N in 1,4-dioxane) and (65 mL, 4N in 1,4-dioxane) wasadded in 30 mins interval stirred at room temperature. The reactionmixture after completion (1 h) was concentrated in vacuum to dryness.The residue obtained was triturated with hexanes (2 L) and solidobtained was collected by filtration, washed with hexanes and driedunder vacuum to afford(−)-N-(5-(amino(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (227b) (489.3 g). An analytical sample was prepared byrecrystallization from isopropanol to furnish (227b) as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.02 (s, 3H), 8.13 (d, J=2.1Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (dd, J=7.2, 2.3 Hz, 1H),7.77 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.67 (d, J=7.0 Hz, 1H), 7.49-7.36(m, 7H), 5.70 (s, 1H); ¹⁹F NMR (282 MHz, DMSO) δ −60.99, −120.98; MS(ES+) 480.2 (M+1); (ES−) 478.2 (M−1); Optical rotation: [α]_(D)=(−) 3.60[1.11, CH₃OH], Analysis calculated for C₂₅H₁₇F₄N₅₀.HCl.1.25H₂O: C,55.77; H, 3.84; Cl, 6.58; N, 13.01; Found: C, 55.87; H, 3.98; Cl, 6.46;N, 12.91.

Step-3: Preparation of(−)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227c)

To a stirred solution of(−)-N-(5-(amino(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227b) [(50.52 g, 105 mmol), which was converted to free base usingaqueous NaHCO₃, extracting with ethyl acetate and drying in vacuum priorto use in reaction)] in methanol (530 mL) was addedcyclopropanecarbaldehyde (9.84 mL, 132 mmol) and stirred at roomtemperature for 5 h. The reaction mixture was quenched with sodiumborohydride (8.14 g, 211 mmol) carefully with ice/water cooling (insidetemp. was between 6° C. and 10° C. during addition) followed by stirringat room temperature for 60 min. Methanol was evaporated in vacuum andresidue was treated with water (1 L) and extracted with ethyl acetate(2×1 L, 0.5 L). The combined organic layers were dried over MgSO₄,filtered and evaporated to dryness. The residue was purified by flashcolumn chromatography (silica gel 2 kg, eluting with ethyl acetate inhexanes from 0-60%) to afford(−)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227c) (39.85 g, 71% yield) as a colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 10.54 (s, 1H, D₂O exchangeable), 8.14-8.07 (m, 1H), 7.97 (dt,J=7.7, 1.3 Hz, 1H), 7.93-7.85 (m, 1H), 7.75-7.66 (m, 2H), 7.58 (dd,J=7.6, 2.2 Hz, 1H), 7.45-7.12 (m, 7H), 4.83 (s, 1H), 2.42 (s, 1H), 2.26(m, 2H), 0.90 (m, 1H), 0.45-0.28 (m, 2H), 0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.86, −123.17; MS (ES⁺): MS (ES+) 534.2 (M+1); 532.2(M−1); Optical rotation: [α]_(D)=(−) 7.83 [0.23, MeOH].

Step-4: Preparation of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d)

To a solution of(−)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227c) (1.0 g, 1.874 mmol) in THF (15 mL) was added LiHMDS (1 M in THF,4.00 mL, 4.00 mmol) and stirred at room temperature for 24 h. AdditionalLiHMDS (1 M in THF, 4.00 mL, 4.00 mmol) was added and reaction washeated at reflux for 5.5 h. The reaction mixture was cooled to roomtemperature and concentrated in vacuum to dryness. The residue wasacidified with 1N KHSO₄ (15 mL) and extracted with ethyl acetate (2×30mL). The organic layers were combined, dried over anhydrous MgSO₄,filtered and evaporated to dryness. The residue obtained was purified byflash column chromatography (silica gel 25 g, eluting with CMA80 inCHCl₃ from 0 to 100%)] to(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (0.205 g, 20% yield) free base as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.97 (t, J=1.8 Hz, 1H), 7.91 (dt, J=7.6, 1.5 Hz, 1H),7.59 (dd, J=15.0, 7.7 Hz, 4H), 7.43-7.36 (m, 2H), 7.35-7.25 (m, 3H),7.23-7.14 (m, 2H), 4.83 (s, 1H), 2.26 (d, J=6.1 Hz, 2H), 0.90 (m, 1H),0.42-0.32 (m, 2H), 0.07-0.01 (m, 2H); MS (ES+): 551.4 (M+1); 549.4(M−1).

Preparation of HCl salt of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d)

To a stirred solution of free base of 227d (0.152 g, 0.276 mmol) inethanol (5 mL) was added conc. HCl (0.115 mL, 1.380 mmol) and stirred atroom for 10 min. The solution was evaporated to dryness to afford(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (0.165 g, 0.248 mmol, 90% yield) hydrochloride salt as a yellowsolid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H, D₂O exchangeable), 10.20 (s,2H, D₂O exchangeable), 9.53 (s, 2H, D₂O exchangeable), 9.29 (s, 2H, D₂Oexchangeable), 8.03 (t, J=1.9 Hz, 1H), 7.97 (dt, J=8.0, 1.4 Hz, 1H),7.89 (ddd, J=9.2, 7.3, 2.1 Hz, 2H), 7.82 (s, 1H), 7.80-7.67 (m, 4H),7.50-7.32 (m, 4H), 5.65 (t, J=6.5 Hz, 1H), 2.71 (d, J=11.3 Hz, 2H),1.18-1.13 (m, 1H), 0.65-0.45 (m, 2H), 0.30 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.87, −120.21; MS (ES+) 551.4 (M+1); MS (ES−) 549.34 (M−1),585.36 (M+Cl); Optical rotation: [α]_(D)=(−) 1.57 [0.51, CH₃OH];Analysis calculated for C₂₉H₂₆F₄N₆O.2HCl.2.25H₂O: C, 52.46; H, 4.93; N,12.66; Found: C, 52.62; H, 4.89; N, 12.27.

Preparation of(+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(228a)

To a stirred solution of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(212g) (80 mg, 0.123 mmol) in ethanol (10 mL) was added ammoniumhydroxide (10 mL, 257 mmol) hydrogen peroxide (1 mL, 32.6 mmol) andstirred at room temperature overnight. Additional hydrogen peroxide (1mL, 32.6 mmol) was added to the reaction mixture and continued stirringfor 24 h. The reaction was concentrated in vacuum; residual water wasremoved by azeotropic distillation with ethanol (50 mL). The cruderesidue obtained was purified by flash column chromatography (silica gel12 g, eluting with CMA 80 in chloroform) to afford(+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(228a) (32 mg, 0.054 mmol, 43.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.52 (s, 1H), 7.90 (s, 1H), 7.79-7.72 (m, 2H), 7.55 (d,J=5.9 Hz, 2H), 7.50 (s, 1H), 7.42 (dd, J=7.9, 2.6 Hz, 4H), 7.36-7.24 (m,3H), 7.16 (t, J=9.4 Hz, 1H), 3.77 (s, 2H), 2.32-2.11 (m, 4H), 1.13-0.90(m, 2H), 0.62 (m, 1H), 0.42-0.25 (m, 2H), −0.09 (m, 2H); 19F NMR (282MHz, DMSO-d₆) δ −60.72, −124.35 (q, J=9.8, 7.8 Hz); MS (ES+) 595.5(M+1), 617.5 (M+Na); Optical rotation: [α]_(D)=(+) 8.57 [0.21, CH₃OH].

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N₅-(5-((cyclopropylmethylamino)(phenyl)-methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229i) Step-1: Preparation of Lithium(Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-en-1-olate (229b)

To LiHMDS (134 mL, 134 mmol, 1 M solution in THF) in diethyl ether (410mL) cooled to −78° C. was added 1-(furan-2-yl)ethanone (229a) (14 g, 127mmol) in one portion and stirred for 5 mins. To this was added asolution of di-tert-butyl oxalate (25.7 g, 127 mmol) in diethyl ether(100 mL). The reaction mixture was allowed to warm to room temperatureovernight. The mixture was filtered and the resulting yellow solid waswashed with ether (100 mL), dried in vacuum to afford lithium(Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-en-1-olate (229b) (23.6g, 97 mmol, 76% yield) which was used as such for next step; ¹H NMR (300MHz, DMSO-d₆) δ 7.75 (dd, J=1.7, 0.8 Hz, 1H), 6.95 (dd, J=3.4, 0.9 Hz,1H), 6.56 (dd, J=3.4, 1.7 Hz, 1H), 6.24 (s, 1H), 1.46 (s, 9H); MS (ES−)237.059 (M−1).

Step-2: Preparation of tert-Butyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (229d)

To lithium (Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-en-1-olate(229b) (21.59 g, 88 mmol) and 3-hydrazinylbenzonitrile hydrochloride(229c) (15 g, 88 mmol) was added AcOH (400 mL) and stirred at roomtemperature overnight. The mixture was concentrated in vacuum and theresidue obtained was purified by flash column chromatography (silica gel300 g, eluting with 25% ethyl acetate in hexane) to furnish tert-butyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (229d)(24.658 g, 73.5 mmol, 83% yield) as an yellow oil, which solidified onstanding; ¹H NMR (300 MHz, DMSO-d₆) δ 8.10-7.98 (m, 2H), 7.88-7.72 (m,3H), 7.15 (s, 1H), 6.56 (dd, J=3.5, 1.8 Hz, 1H), 6.41 (dd, J=3.4, 0.8Hz, 1H), 1.55 (s, 9H); MS (ES+) 358.3 (M+Na).

Step-3: Preparation of1-(3-Cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic Acid (229e)

To a solution of tert-butyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (229d) (23 g,68.6 mmol) in dichloromethane (250 mL) was added trifluoroacetic acid(211 mL, 2743 mmol) and stirred at room temperature for 5 h. Thereaction was concentrated in vacuum to dryness to furnish1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic acid (229e)(19.0 g, 68.0 mmol, 99% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.07-8.00 (m, 2H), 7.87-7.71 (m, 3H), 7.19 (s, 1H), 6.58 (dd,J=3.5, 1.8 Hz, 1H), 6.46 (dd, J=3.5, 0.8 Hz, 1H); MS (ES+) 280.3 (M+1);302.2 (M+Na).

Step-4: Preparation of1-(3-Cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxamide (229f)

To a solution of1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic acid (229e)(13 g, 46.6 mmol) in dichloromethane (75 mL) was added oxalyl chloride(2 M solution in dichloromethane, 46.6 mL, 93 mmol) followed by DMF (10drops). The reaction mixture was stirred at room temperature for 5 h andconcentrated in vacuum to dryness. The residue obtained was dissolved indichloromethane (250 mL), added ammonia in dioxane (0.5 M solution, 233mL, 116 mmol) and stirred at room temperature overnight. The reactionmixture was concentrated in vacuum and the residue was poured intowater. The aqueous layer was extracted with ethyl acetate (3×100 mL).The organic layers were combined washed with brine (100 mL), dried,filtered and concentrated in vacuum to afford1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxamide (229f) (10.2g, 36.7 mmol, 79% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.08 (ddd, J=2.2, 1.6, 0.6 Hz, 1H), 8.01 (dt, J=7.4, 1.5 Hz, 1H),7.85-7.72 (m, 4H), 7.52-7.40 (m, 1H), 7.12 (s, 1H), 6.58 (dd, J=3.5, 1.8Hz, 1H), 6.44 (dd, J=3.5, 0.8 Hz, 1H); MS (ES+) 279.3 (M+1); 301.3(M+Na); (ES−) 277.4 (M−1).

Step-5: Preparation of3-Carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g)

To a solution of1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxamide (229f) (7.5g, 27.0 mmol) in Water (150 mL) and t-BuOH (150 mL) was added sodiumdihydrogen phosphate (5% aqueous, 105 mL, 53.6 mmol). The resultingsolution was warmed to 60° C. and added potassium permanganate (20.31 g,129 mmol) in small portions over a period of 30 mins. The slurry wasstirred for 30 mins cooled to 0° C. and quenched with saturated aqueoussodium bisulfite (428 mL, 2142 mmol). The resulting mixture wasfiltered, washed with water (300 mL), and filtrate was acidified withConc. HCl. The solid obtained was collected by filtration to afford ondrying 3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid(229g) (2.48 g, 9.68 mmol, 45.2% yield) as a white solid. The aqueouslayer was concentrated in vacuum to about 50 mL and extracted with ethylacetate (5×50 mL). The organic layers were combined dried, filtered andconcentrated in vacuum to afford3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g) (2.9g, 11.32 mmol, 52.8% yield) as a second crop which was pure enough to beused for next step; ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.01-7.86(m, 3H), 7.72 (t, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.33 (s, 1H); MS (ES−)255.1 (M−1).

Step-6: Preparation of1-(3-cyanophenyl)-N5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229h)

Compound 229h was prepared from3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g)(0.606 g, 2.364 mmol) and(−)-5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluoroaniline (222f)(0.581 g, 2.149 mmol) as described in step-3 of scheme-208 to afford1-(3-cyanophenyl)-N₅-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229h) (0.706 g, 65% yield) as a yellow syrup which was used as such inthe next step; ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.10 (s, 1H),7.95 (dt, J=7.7, 1.3 Hz, 1H), 7.87 (d, J=7.1 Hz, 2H), 7.70 (t, J=7.9 Hz,1H), 7.62-7.49 (m, 3H), 7.44-7.13 (m, 7H), 4.84 (s, 1H), 2.35-2.20 (m,2H), 1.02-0.85 (m, 1H), 0.51-0.28 (m, 2H), 0.05 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −123.18; MS (ES+): 509.4.

Step-7: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N₅-(5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229i)

Compound 229i was prepared from1-(3-cyanophenyl)-N₅-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229h) (0.681 g, 1.339 mmol) according to the procedure reported forpreparation of compound 15g in step-6 of scheme-15 to furnish(−)-1-(3-(aminomethyl)phenyl)-N5-(5-((cyclopropyl-methylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide(229i) (89 mg, 13% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.42 (s, 1H, D₂O exchangeable), 7.79 (s, 1H), 7.64-7.55 (m, 1H), 7.49(d, J=7.0 Hz, 2H), 7.45-7.36 (m, 5H), 7.35-7.24 (m, 4H), 7.18 (td,J=8.5, 2.3 Hz, 2H), 4.83 (s, 1H), 3.79 (s, 2H), 2.27 (m, 2H), 0.91 (m,1H), 0.47-0.27 (m, 2H), 0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.40; MS (ES+) 513.4 (M+1); MS (ES−) 511.5 (M−1); Optical rotation:[α]_(D)=(−) 4.17 [0.24, CH₃OH]; Analysis calculated for:C₂₉H₂₉FN₆O₂.1.5H₂O: C, 64.55; H, 5.98; F, 3.52; N, 15.57; Found: C,64.34; H, 5.95; F, 4.40; N, 15.62.

Preparation of(−)-1-(3-carbamoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(230a)

To a stirred solution of(−)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227c) (1.067 g, 2.0 mmol) in ethanol (50 mL) was added ammoniumhydroxide (19 mL, 257 mmol) hydrogen peroxide (0.700 mL, 7.92 mmol) andstirred at room temperature for 22 h. The reaction was concentrated invacuum and crude residue obtained was purified by flash columnchromatography (silica gel 25 g, eluting with CMA 80 in chloroform) toafford(−)-1-(3-carbamoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(230a) (108 mg, 0.196 mmol, 9.79% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.15 (s, 1H), 8.04-7.97 (m, 2H),7.70-7.52 (m, 5H), 7.42-7.36 (m, 2H), 7.35-7.13 (m, 5H), 4.83 (s, 1H),2.32-2.20 (m, 2H), 0.97-0.78 (m, 1H), 0.44-0.29 (m, 2H), 0.07-0.00 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.63, −123.40; MS (ES+): 552.4 (M+H);Optical rotation: [α]_(D)=(−) 6.51 (0.215, Methanol); Analysiscalculated for C₂₉H₂₅F₄N₅O₂: C, 63.15; H, 4.57; N, 12.70. Found: C,62.97; H, 4.57; N, 12.72.

Preparation of(+)-N⁵-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-1H-pyrazole-3,5-dicarboxamide(231d) Step-1 Preparation of tert-butyl3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a)

To a solution of1-(3-Cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxamide (229f) inmethanol (100 mL) cooled with ice/water was added nickel(II) chloridehexahydrate (0.322 g, 1.353 mmol) and Boc anhydride (3.14 mL, 13.53mmol) followed by portionwise addition of sodium borohydride (2.56 g,67.6 mmol) over a period of 15 min. The reaction mixture was stirred atroom temperature for 2 h and quenched withN1-(2-aminoethyl)ethane-1,2-diamine (4.38 mL, 40.6 mmol) followed bystirring for additional 0.5 h. The reaction mixture was concentrated invacuum to dryness. The residue was treated with water (50 mL), andextracted with ethyl acetate (2×100 mL). The organic layers werecombined dried, filtered and concentrated in vacuum to dryness. Theresidue was purified by flash column chromatography (silica gel 25 g,eluting with methanol in chloroform from 0 to 25%) to furnish tert-butyl3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a)(1.8 g, 4.71 mmol, 69.6% yield) as a colorless solid. ¹H NMR (300 MHz,DMSO-d₆) δ 7.73 (dd, J=1.9, 0.8 Hz, 2H), 7.49 (dd, J=9.0, 6.4 Hz, 2H),7.45-7.38 (m, 2H), 7.36 (d, J=1.8 Hz, 1H), 7.31 (dd, J=7.8, 1.7 Hz, 1H),7.06 (s, 1H), 6.50 (dd, J=3.5, 1.8 Hz, 1H), 6.13 (d, J=3.5 Hz, 1H), 4.19(d, J=6.2 Hz, 2H), 1.37 (s, 9H).

Step-2 Preparation of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-carbamoyl-1H-pyrazole-5-carboxylicAcid (231b)

To a solution of furnish tert-butyl3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a)(0.65 g, 1.70 mmol), sodium dihydrogen phosphate (1.02 g, 8.50 mmol) inacetonitrile (10 mL) and water (2 mL) was added a solution of sodiumchlorite (1.537 g, 17.00 mmol) in water (10.00 mL) and stirred at roomtemperature overnight. The reaction was evaporated to dryness. Theresidue was treated with sat. NaHCO₃, extracted with chloroform (2×50mL). The combined organics were dried, filtered, evaporated to dryness.The residue was purified by flash chromatography {silica gel 24 g,eluting with CMA80 in chloroform, 0-100%) to afford1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-carbamoyl-1H-pyrazole-5-carboxylicacid (231b) (225 mg, 0.624 mmol, 36.7% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.83 (s, 1H), 7.49 (td, J=18.8, 17.7, 8.7Hz, 3H), 7.39-7.34 (m, 2H), 4.19 (d, J=6.3 Hz, 2H), 1.39 (s, 9H); MS(ES+) 383.3 (M+Na), (ES−) 359.3 (M−1).

Step-3 Preparation of tert-butyl3-(3-carbamoyl-5-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(231c)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-carbamoyl-1H-pyrazole-5-carboxylicacid (231b) (210 mg, 0.582 mmol) in N,N-dimethylformamide (4.10 mL, 52.9mmol) was added(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (219 mg, 0.529 mmol), N-ethyl-N-isopropylpropan-2-amine (0.461mL, 2.65 mmol) and bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop) (296 mg, 0.635 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 12h under nitrogen atmosphere. The reaction was diluted with water (40 mL)and extracted with ethyl acetate (2×50 mL). The organic layers werecombined, washed with brine (25 mL), dried, filtered, and concentratedin vacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel 25 g, eluting with 0-100% ethyl acetate inhexanes) to furnish tert-butyl3-(3-carbamoyl-5-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(231c) (78 mg, 0.103 mmol, 19.49% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.48 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.3 Hz,2H), 7.64-7.46 (m, 2H), 7.48-7.27 (m, 6H), 7.21 (d, J=7.6 Hz, 2H), 5.56(s, 1H), 4.17 (d, J=6.3 Hz, 2H), 2.71-2.39 (m, 2H), 1.37 (s, 9H),1.35-1.13 (m, 1H), 1.12 (s, 9H), 0.98-0.77 (m, 1H), 0.72-0.51 (m, 1H),0.42-0.25 (m, 2H), −0.03-−0.19 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−122.74; MS (ES+) 778.6 (M+Na).

Step-4 Preparation of(+)-N⁵-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-1H-pyrazole-3,5-dicarboxamide(231d)

To a solution of tert-butyl3-(3-carbamoyl-5-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(231c) (70 mg, 0.093 mmol) in ethanol (5 mL) was added Conc. HCl (0.077mL, 0.924 mmol), stirred for 1 h and concentrated in vacuum to dryness.The residue was purified by flash column chromatography (silica gel) toafford 231d (50 mg, 0.091 mmol, 98% yield) free base an off white solid;¹H NMR (300 MHz, DMSO-d₆) δ 10.41 (s, 1H), 7.86-7.69 (m, 3H), 7.57 (d,J=8.1 Hz, 3H), 7.48 (s, 2H), 7.40 (dd, J=6.3, 4.1 Hz, 3H), 7.27 (ddt,J=15.5, 4.7, 2.4 Hz, 2H), 7.17 (t, J=9.4 Hz, 1H), 3.76 (s, 2H), 2.57 (m,2H), 2.23 (m, 2H), 1.06-0.89 (m, 2H), 0.5-0.6 (m, 1H), 0.44-0.28 (m,2H), −0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −123.86; MS (ES−)550.4, 551.5 (M−1).

To a solution of free base was in ethanol (5 mL) was added Conc. HCl(0.077 mL, 0.924 mmol), stirred for 5 mins and concentrated in vacuum todryness. The residue was dissolved in water (1 mL) and dried undervacuum to furnish(+)-N⁵-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-1H-pyrazole-3,5-dicarboxamide (231d) (0.046 g, 0.074 mmol, 80% yield) hydrochloride asan off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.48 (s,3H), 8.48 (s, 3H), 7.97-7.91 (m, 2H), 7.80-7.75 (m, 1H), 7.71 (t, J=1.8Hz, 1H), 7.63-7.45 (m, 8H), 7.43-7.26 (m, 2H), 4.09 (q, J=5.7 Hz, 2H),2.65-2.52 (m, 2H), 1.26-0.95 (m, 2H), 0.77-0.60 (m, 1H), 0.47-0.27 (m,2H), 0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −120.20; MS (ES+) 552.5(M+1); (ES−) 550.3 (M−1); Optical rotation: [α]_(D)=(+) 18.67 [0.225,MeOH].

Preparation of(−)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(232a)

To a stirred solution of(−)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227c) (1 g, 1.874 mmol) in ethanol (15 mL) was added hydroxylamine(1.10 mL, 18.65 mmol) and heated at reflux for 1 h. The reaction wasconcentrated in vacuum and crude residue obtained was purified by flashcolumn chromatography [silica gel 25 g, eluting with hexanes/ethylacetate (1:0 to 1:1)] to afford compound 232a (873 mg, 1.1541 mmol, 82%yield) free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s,1H), 9.84 (s, 1H), 7.87-7.83 (m, 1H), 7.80 (td, J=4.4, 1.7 Hz, 1H),7.65-7.58 (m, 2H), 7.51-7.48 (m, 2H), 7.41-7.13 (m, 7H), 5.93 (s, 2H),4.83 (s, 1H), 2.32-2.21 (m, 2H), 0.98-0.80 (m, 1H), 0.44-0.28 (m, 2H),0.10-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.61, −123.51; MS(ES+) 567.4 (M+1), 565.3 (M−1).

To a solution of free base of 232a (400 mg, 0.71 mmol) in methanol (10mL) was added 4 N aqueous HCl (aqueous 0.71 mL) and concentrated invacuum to dryness to afford(−)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(232a) (427 mg, 89.53% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 11.25 (s, 1H), 10.81 (s, 1H), 10.14 (s, 2H),8.98 (s, 1H), 7.94 (t, J=1.9 Hz, 1H), 7.91-7.80 (m, 3H), 7.80-7.66 (m,5H), 7.48-7.31 (m, 4H), 5.69-5.62 (m, 1H), 2.77-2.60 (m, 2H), 1.23-1.09(m, 1H), 0.62-0.47 (m, 2H), 0.37-0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.70, −120.13; MS (ES−) 565.4 (M−1), 601.3 (M+Cl); Optical rotation:[α]_(D)=(−) 0.38 (0.52, Methanol); Analysis calculated forC₂₉H₂₆F₄N₆O₂.2HCl.2H₂O: C: 51.56; H: 4.77; N: 12.44; Found C: 51.21; H:4.82; N: 12.00.

Preparation of (−)-ethyl(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(233a)

To a solution of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (200 mg, 0.363 mmol) in acetonitrile (10 mL) was addedtriethylamine (0.160 mL, 1.148 mmol), ethyl carbonochloridate (0.036 mL,0.363 mmol) and stirred at room temperature for 14 h. The reaction wasdiluted with ethyl acetate (120 mL) washed with water (60 mL). Theaqueous layer was extracted again with ethyl acetate (60 mL). Thecombined organic layers were washed with brine (60 mL), dried overMgSO₄, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica gel, 12 g eluting withhexanes/ethyl acetate (1:0 to 1:1)] to afford compound 233a (130 mg,0.209 mmol, 57.5%) free base as an off white solid. The solid (55 mg,0.088 mmol) was dissolved in methanol (8 mL) added 4 N aqueous HCl(0.088 mL) and concentrated in vacuum to dryness to afford (−)-ethyl(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(233a) (60 mg, 92.23%) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 11.29 (s, 1H), 10.84 (s, 1H), 10.67-10.36 (m, 2H), 10.18 (d, 2H), 8.05(t, J=1.9 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.88 (dd, J=7.3, 2.2 Hz, 2H),7.80 (s, 1H), 7.78-7.66 (m, 4H), 7.48-7.31 (m, 4H), 5.68-5.62 (m, 1H),4.30 (q, J=7.1 Hz, 2H), 2.76-2.63 (m, 2H), 1.30 (t, J=7.1 Hz, 3H),1.22-1.02 (m, 1H), 0.66-0.45 (m, 2H), 0.30 (dt, J=6.1, 4.4 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.86, −120.22; MS (ES+): 623.5 (M+1); Opticalrotation: [α]_(D)=(−) 13 [0.2, CH₃OH]; Analysis calculated forC₃₂H₃₀F₄N₆O₃.2HCl.2.25H₂O: C, 52.22; H, 5.00; Cl, 9.63; N, 11.42; FoundC: 52.29; H: 4.85 N: 11.66; Cl: 9.27.

Preparation of (−)-Hexyl(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(233b)

To a solution of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (150 mg, 0.27 mmol) in anhydrous acetonitrile (10 mL) was addedtriethylamine (88 mg, 0.87 mmol) followed by a solution of hexylchloroformate (45 mg, 0.27 mmol) in anhydrous acetonitrile (3.0 mL). Thereaction mixture was stirred for 11 h at room temperature, diluted withEtOAc (40 mL) and washed with water (20 mL). The aqueous layer wasextracted again with EtOAc (20 mL) and combined organic layers weredried over MgSO₄, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography [silica gel 12g,eluting with 0-50% (ethyl acetate/MeOH (9:1, v/v) in hexanes) to obtainfree base of 233b as a free base. The free base was dissolved MeOH added3N HCl in MeOH (5.0 mL), stirred for 4 h at room temperature andconcentrated in vacuum to furnish (−)-Hexyl(3-(5-(5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(233b) (126 mg, 59% yield) hydrochloride as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 10.23 (d, J=23.1 Hz, 2H),8.05 (t, J=2.0 Hz, 1H), 7.98-7.69 (m, 7H), 7.53-7.27 (m, 4H), 5.65 (s,1H), 4.23 (s, 2H), 2.69 (s, 2H), 1.66 (s, 2H), 1.46-1.22 (m, 6H),0.93-0.79 (m, 3H), 0.62-0.47 (m, 2H), 0.30 (d, J=5.1 Hz, 2H), 0.00 (s,2H); MS (ES+) 304.9 (M/2-2H₂O), 340.4 (M/2+1), 679.5 (M+1); Opticalrotation: [t]_(D)=(−) 7.77 [0.515, CH₃OH]; Analysis calculated forC₃₆H₃₈F₄N₆O₃.2HCl.2H₂O: C, 54.89; H, 5.63; Cl, 9.00; N, 10.67; Found: C,54.92; H, 5.51; Cl, 8.80; N, 10.60.

Preparation of (−)-2,2,2-trichloroethyl((3-(5-((5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluoro-phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamate(233c)

To a solution of(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)-(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (150 mg, 0.27 mmol) in anhydrous acetonitrile (10 mL) was addedtriethylamine (88 mg, 0.87 mmol) followed by addition of a solution of2,2,2-trichloroethyl chloroformate (57.6 mg, 0.27 mmol) in anhydrousacetonitrile (3.0 mL). The resulting reaction mixture was stirred for 11h at room temperature. Work up, purification and conversion tohydrochloride salt as reported in preparation for compound 233b gave(−)-2,2,2-trichloroethyl((3-(5-((5-(((cyclopropylmethyl)amino)-(phenyl)methyl)-2-fluoro-phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamate(233c) (106 mg, 54% yield) hydrochloride salt as a white solid. ¹H NMR(300 MHz, DMSO-d₆ one drop of D₂O) δ 8.22-7.96 (m, 2H), 7.87 (dq, J=6.1,3.0 Hz, 1H), 7.83-7.60 (m, 6H), 7.40 (dt, J=13.3, 7.7 Hz, 4H), 5.64 (s,1H), 4.99 (s, 1H), 4.90 (s, 1H), 2.70 (d, J=7.0 Hz, 2H), 1.19-1.02 (m,1H), 0.67-0.41 (m, 2H), 0.37-0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.63, −60.65, −120.48; MS (ES+) 727.4 (M+1); Optical rotation:[α]_(D)=(−) 12.63 [0.285, CH₃OH]; Analysis calculated forC₃₂H₂₇C₁₃F₄N₆O₃.1.8HCl.2H₂O: C, 46.44; H, 3.99; Cl, 20.56; N, 10.15;Found: C, 46.39; H, 4.0; Cl, 20.60; N, 10.16.

Preparation of (−)-S-ethyl((3-(5-((5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamothioate(233d)

Compound 233d was prepared from(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (220.0 mg, 0.40 mmol) and ethyl chlorothioformate (49.8 mg, 0.40mmol) according to the procedure described in preparation of compound233b afforded (−)-S-ethyl((3-(5-((5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamothioate(233d) (120 mg, 47% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 11.90 (s, 1H), 10.89 (s, 1H), 10.29 (bs, 2H),8.13-7.98 (m, 2H), 7.92-7.62 (m, 7H), 7.49-7.30 (m, 4H), 5.77-5.52 (m,1H), 2.87 (m, 2H), 2.77-2.59 (m, 2H), 1.29-1.22 (m, 3H), 1.22-1.11 (m,1H), 0.64-0.42 (m, 2H), 0.40-0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−60.66, −60.68, −120.13; MS (ES+) 639.4 (M+1); Optical rotation:[α]_(D)=(−) 5.44 [0.515, CH₃OH]; Analysis calculated forC₃₂H₃₀F₄N₆O₂S.2HCl.2H₂O: C, 51.41; H, 4.85; Cl, 9.48; N, 11.24; S, 4.29;Found: C, 51.33; H, 4.76; Cl, 9.21; N, 11.41; S, 4.15.

Preparation of(−)-1-((3-(5-(5-((−)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamoyloxy)ethyl acetate (233e)

To(−)-1-(3-carbamimidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(227d) (245 mg, 0.445 mmol) was added to NaOH (0.1N, 5.3 mL) andresulting mixture was stirred for 10 min at room temperature. Thereaction mixture was concentrated in vacuum and residue obtaineddissolved in HMPA (10 mL). To the solution was added1-((4-nitrophenoxy)carbonyloxy)ethyl acetate [prepared as reported byRahrmathullah, Syed M. et al in Journal of Medicinal Chemistry, 42(19),3994-4000; 1999), 240 mg, 0.89 mmol] and stirred at room temperatureovernight. The reaction mixture was quenched with water and extractedwith EtOAc (3×30 mL). The organic layers were combined washed with brine(20 mL), dried and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel, eluting with 0-100%EtOAc in hexane) to afford(−)-1-((3-(5-(5-((−)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamoyloxy)ethyl acetate (233e) (212 mg, 0.311 mmol, 70.0% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H), 9.47-9.34 (m,2H), 8.21-8.08 (m, 2H), 7.82-7.54 (m, 4H), 7.39 (d, J=7.0 Hz, 2H), 7.28(t, J=7.5 Hz, 2H), 7.24-7.14 (m, 2H), 6.77 (q, J=5.4 Hz, 1H), 4.84 (s,1H), 2.27 (m, 2H), 2.02 (s, 3H), 1.43 (d, J=5.4 Hz, 3H), 0.88 (m, 1H),0.43-0.26 (m, 2H), 0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.64,−123.32; MS (ES+) 681.5 (M+1); Optical rotation: [α]_(D)=(−) 5.37[0.335, MeOH].

Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(234d) Step-1 Preparation of tert-butyl3-(3-cyano-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (234a)

To a solution of furnish tert-butyl3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a)(200 mg, 0.523 mmol) in THF (4 mL) was added pyridine (0.085 mL, 1.046mmol), 2,2,2-trifluoroacetic anhydride (0.089 mL, 0.628 mmol) dropwiseand stirred at room temperature for 30 mins. The reaction was quenchedwith water (1 mL) and concentrated in vacuum to dryness. To the residuewas added saturated aqueous NaHCO₃ (20 mL) and extracted with chloroform(2×30 mL). The combined chloroform layers were washed with brine (30mL), dried over MgSO₄ filtered and concentrated in vacuum. The residuewas purified by flash column chromatography (silica gel 12 g, elutingwith ethyl acetate in hexane 0 to 100%) to furnish tert-butyl3-(3-cyano-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (234a) (120mg, 0.329 mg, 63.0%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.79(dd, J=1.8, 0.8 Hz, 1H), 7.57-7.42 (m, 4H), 7.40-7.31 (m, 2H), 6.53 (dd,J=3.5, 1.8 Hz, 1H), 6.15 (d, J=3.5 Hz, 1H), 4.20 (d, J=6.2 Hz, 2H), 1.37(s, 9H); MS (ES+): 387.3 (M+Na).

Step-2 Preparation of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylicAcid (234b)

Compound 234b was prepared from tert-butyl3-(3-cyano-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (234a) (115mg, 0.316 mmol) as described in step-5 of scheme-229 to furnish1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylicacid (234b) (135 mg) as a yellow solid, which was used as such for nextstep; MS (ES−) 341.3 (M−1), 683.3 (2M−1).

Step-3: Preparation of tert-butyl3-(3-cyano-5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(234c)

Compound 234c was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylicacid (234b) (0.117 g, 0.341 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (0.103 g, 0.249 mmol) as described in step-3 of scheme-208 tofurnish tert-butyl3-(3-cyano-5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(234c) (90 mg, 0.122 mmol, 49.0%) as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.64 (s, 1H), 7.81-7.32 (m, 11H), 7.23 (d, J=7.5 Hz,2H), 5.55 (s, 1H), 4.18 (d, J=6.1 Hz, 2H), 2.65-2.40 (m, 2H), 1.38 (s,9H), 1.12 (s, 9H), 1.08-0.76 (m, 2H), 0.63 (s, 1H), 0.39-0.30 (m, 2H),−0.02-−0.21 (m, 2H); MS (ES+): 760.6 (M+Na); Optical rotation:[α]_(D)=(−) 43.81 [0.105, MeOH].

Step-4: Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(234d)

To a solution of tert-butyl3-(3-cyano-5-(5-((−)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(234c) (78 mg, 0.106 mmol) in ethanol (10 mL) was added conc. HCl (0.090mL, 1.078 mmol) heated at reflux for 1 h and concentrated in vacuum todryness. The residue was purified twice by flash column chromatography[silica gel, first column, eluting with chloroform/CMA80 (1:0 to 3:1),second column eluting with chloroform/methanol (1:0 to 9:1)] to afford234d (25 mg, 0.047 mmol, 44.3% yield) free base an off white solid; Freebase (25 mg, 0.047 mmol) was dissolved in ethanol (3 mL), added conc.HCl (aq. 0.020 mL) and concentrated in vacuum to dryness. The residuewas dissolved in 3 mL of water and concentrated in vacuum to dryness tofurnish(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(234d) (28 mg, 95.69%) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.83 (s, 1H), 9.33 (s, 3H), 8.31 (s, 3H), 7.96 (d,J=8.3 Hz, 2H), 7.90-7.20 (m, 10H), 4.17-4.07 (m, 2H), 2.60-2.40 (m, 2H),1.35-0.93 (m, 2H), 0.75-0.60 (m, 1H), 0.42-0.32 (m, 2H), 0.04-−0.06 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −120.21; MS (ES+): 534.5 (M+1);Optical rotation: [α]_(D)=(+) 15.85 [0.265, MeOH].

Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235) Step-1: Preparation of(E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b)

A mixture of 2-methyl-5-nitrobenzonitrile (235a) (5 g, 30.8 mmol) and1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent)(10.19 mL, 49.3 mmol) in dry DMF (10 mL) was heated at 70° C. for 2 h.The reaction was cooled to room temperature and concentrated in vacuum;the crude product was triturated with 120 mL of hexanes/ethyl acetate(5:1), and stirred for 10 min. The solid obtained was collected byfiltration washed with hexanes (2×75 mL), dried under vacuum to afford(E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b) (6.07 g, 91%yield) as a light brown solid; ¹H NMR: ¹H NMR (300 MHz, DMSO-d₆) δ 8.35(d, J=2.5 Hz, 1H), 8.06 (ddd, J=9.2, 2.6, 0.7 Hz, 1H), 7.93 (d, J=13.0Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 5.29 (d, J=12.9 Hz, 1H), 3.04 (s, 6H);MS (ES−) 252.1 (M+Cl).

Step-2: Preparation of2-(2,4-Dimethoxybenzyl)-7-nitroisoquinolin-1(2H)-imine (235c)

A mixture of (E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b)(6.01 g, 27.7 mmol) and (2,4-dimethoxyphenyl)methanamine (5.45 mL, 34.6mmol) in 1,3-dimethyltetrahydropyrimidin-2(1H)-one (DMPU) (10 mL, 80mmol) was heated at 140° C. for 3 h. The solvent was removed by vacuumdistillation and residue obtained was purified by flash columnchromatography [silica gel 120 g, eluting with methanol in chloroform,0-100%] to furnish2-(2,4-Dimethoxybenzyl)-7-nitroisoquinolin-1(2H)-imine (235c)_(4.26 g,45% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.07 (d, J=2.4Hz, 1H), 8.26 (dd, J=8.7, 2.3 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.38 (d,J=7.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.48 (dd,J=8.4, 2.4 Hz, 1H), 6.22 (d, J=7.4 Hz, 1H), 4.96 (s, 2H), 3.83 (s, 3H),3.74 (s, 3H); MS (ES⁺): MS (ES+) 340.27 (M+1).

Step-3: Preparation of2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-amine (235d)

To a solution of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-1(2H)-imine(4.18 g, 12.32 mmol) in methanol (50 mL) was added palladium (10% Pd oncarbon; 0.787 g). The reaction mixture was hydrogenated at 60 psi for 4h at room temperature. The reaction mixture was filtered through a smallCelite pad rinsed with methanol (2×75 mL) and concentrated under reducedpressure to afford2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-amine(235d)_(3.786 g, 99% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.21 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H),6.87-6.75 (m, 2H), 6.58 (d, J=2.4 Hz, 1H), 6.44 (dd, J=8.4, 2.4 Hz, 1H),5.97 (d, J=7.4 Hz, 1H), 5.32 (s, 2H, D₂O exchangeable), 4.94 (s, 2H),3.82 (s, 3H), 3.72 (s, 3H), 3.17 (d, J=4.9 Hz, 1H); MS (ES⁺): MS (ES+)310.3 (M+1).

Step-4: Preparation of2-(2,4-dimethoxybenzyl)-7-hydrazinylisoquinolin-1(2H)-iminehydrochloride (235e)

To a suspension of2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-amine (235d)(3.21 g, 10.38 mmol) in conc. HCl (9.51 mL, 114 mmol) at 0° C. was addeddrop-wise a solution of Sodium nitrite (0.716 g, 10.38 mmol) in water(15 mL). The reaction mixture was stirred for 30 min at 0° C. and addedat 0° C. a solution of Tin(II) chloride dihydrate (7.02 g, 31.1 mmol) in12N HCl (6.05 mL, 72.6 mmol). The reaction mixture was stirred at 0° C.for 10 mins and placed in refrigerator overnight. The solid obtained wascollected by filtration, washed with cold brine, cold water and hexanes.The solid was dried over P205 to afford2-(2,4-dimethoxybenzyl)-7-hydrazinylisoquinolin-1(2H)-iminehydrochloride (235e) as a light brown solid which was used as such fornext step; ¹H NMR (300 MHz, DMSO-d₆) δ 10.30 (s, 3H, D₂O exchangeable),9.15 (d, J=29.9 Hz, 3H, D₂O exchangeable), 8.32 (d, J=2.2 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.56 (dd, J=8.7, 2.0 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H),7.20 (d, J=7.3 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H),6.55 (dd, J=8.4, 2.4 Hz, 1H), 5.33 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H);MS (ES⁺): MS (ES+) 325.3 (M+1).

Step-5: Preparation of2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1(2H)-imine(235f)

To a solution of2-(2,4-dimethoxybenzyl)-7-hydrazinylisoquinolin-1(2H)-iminehydrochloride (235e) (3.59 g, 11.07 mmol) in ethanol (50 mL), and conc.HCl (2.77 mL, 33.2 mmol) was added4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (2.509 g, 12.17 mmol) andstirred the at room temperature overnight. The reaction mixture wasconcentrated in vacuum and residue was treated with sat. NaHCO₃,extracted with chloroform (2×150 mL). The combined organics were driedover anhydrous MgSO₄, filtered, evaporated to dryness to afford2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1(2H)-imine(235f) (2.582 g, 47% yield) as a dark yellow waxy solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.32 (s, 1H), 7.77 (dd, J=1.8, 0.7 Hz,1H), 7.61 (d, J=1.3 Hz, 2H), 7.31 (s, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.05(d, J=8.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H),6.47 (dd, J=8.4, 2.4 Hz, 1H), 6.32-6.19 (m, 2H), 4.99 (s, 2H), 3.83 (s,3H), 3.74 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.60; MS (ES⁺): MS(ES+) 495.3 (M+1).

Step-6: Preparation of1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (235e)

To a suspension of2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1(2H)-imine(235f) (15.13 g, 30.6 mmol) in tert-BuOH (200 mL) containing 5% aq.sodium dihydrogenphosphate (6.98 g, 58.2 mmol) in water (140 mL) wasadded solid potassium permanganate (4.84 g, 30.6 mmol) slowly inportions and stirred at room temperature for 4 h. Additional potassiumpermanganate (4.84 g, 30.6 mmol) was added and reaction mixture wasstirred for 2 h. The reaction mixture was quenched with 2-propanol (250mL), stirred for 6 h, filtered through a Celite pad, washed with2-propanol, and acetone. The excess solvents were evaporated and aq.layer was acidified with 1M KHSO₄, crude product extracted with ethylacetate (2×300 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 120 g,eluting with CMA80 in chloroform, 0-100%] to furnish 235e (1.103 g,2.335 mmol, 7.63% yield) as a yellow solid. Compound 235e was dissolvedin chloroform (50 mL) and treated with 30 mL of (1M KHSO₄), the solidobtained was collected by filtration, and dried under vacuum to afford1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (235e) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 2H,D₂O exchangeable), 8.83 (d, J=1.9 Hz, 1H), 8.19-7.96 (m, 2H), 7.67 (d,J=7.3 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.22 (s, 1H), 7.09 (d, J=8.4 Hz,1H), 6.67 (d, J=2.3 Hz, 1H), 6.56 (dd, J=8.5, 2.4 Hz, 1H), 5.33 (s, 2H),3.81 (s, 3H), 3.77 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.67; MS(ES⁺): MS (ES+) 473.3 (M+1); MS (ES−) 471.3 (M−1); Analysis calculatedfor: C₂₃H₁₉F₃N₄O₄.0.5KHSO₄.1.5H₂O: C, 48.68; H, 4.00; N, 9.87; Found: C,48.96; H, 4.09; N, 9.91.

Step-7: Preparation ofN-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235f)

Compound 235f was prepared from1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (235e) (0.269 g, 0.569 mmol) and(−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f)(0.185 g, 0.683 mmol) using procedure reported in step-3 of scheme-208to furnishN-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235f) (0.118 g, 0.163 mmol, 28.6% yield) as a yellow waxy solid whichwas used as such in the next step; MS (ES+): 725.5 (M+1), MS (ES−):723.3 (M−1).

Step-8: Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235)

To a solution ofN-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235f) (0.113 g, 0.156 mmol) in anisole (2 mL) was added trifluoroaceticacid (0.120 mL, 1.559 mmol) and heated at 90° C. for 6 h. The reactionmixture was cooled to room temperature and concentrated in vacuum todryness. The residue was suspended in water (50 mL) basified with sataqueous NaHCO₃ to pH 8.0 and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue obtained was purified by flash columnchromatography [First column: silica gel 12 g, eluting with CMA80 inchloroform; Second column: silica gel 12 g, eluting with ethylacetate/methanol (9:1) in hexanes from 0-100%] to furnish(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(235) (4 mg, 4% yield) as a colorless solid; ¹H NMR (300 MHz, CD₃OD) δ8.35 (d, J=2.4 Hz, 1H), 7.82 (d, J=6.2 Hz, 2H), 7.78-7.69 (m, 2H), 7.45(s, 1H), 7.39-7.31 (m, 2H), 7.31-7.22 (m, 3H), 7.22-7.02 (m, 3H), 4.86(s, 1H), 2.34 (d, J=6.9 Hz, 2H), 1.03-0.84 (m, 1H), 0.53-0.35 (m, 2H),0.04 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −64.53, −128.12; MS (ES⁺): MS(ES+) 575.4 (M+1); MS (ES−) 573.3 (M−1), 609.3 (M+Cl); Optical rotation:[α]_(D)=(−) 0.21 [0.095, MeOH].

Preparation of(+)-1-(3-carbamimidoylphenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(236h) Step-1: Preparation of(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (236a)

To a stirred solution of 3-formylbenzonitrile (45.4 g, 347 mmol) intetrahydrofuran (460 mL) was added(R)-2,4,6-triisopropylbenzenesulfinamide (35 g, 289 mmol),tetraisopropoxytitanium (173 mL, 578 mmol) and heated at reflux for 10h. Work up was performed as reported in step-1 of scheme-222 to furnishafter column chromatography (silica gel 1.5 kg, eluting with 20% ethylacetate in hexane)(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (236a) (37.4 g,160 mmol, 55.3% yield) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (s, 1H), 8.42 (dd, J=1.9, 1.3 Hz, 1H), 8.28 (dt, J=7.9, 1.4 Hz,1H), 8.07 (dt, J=7.7, 1.4 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 1.21 (s, 9H);MS (ES+) 257.2 (M+Na); Optical rotation: [α]_(D)=(−) 83.21 [2.55,CHCl₃].

Step-2: Preparation of(R)—N—((R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(236b) and(R)—N—((S)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(R)—N—((S)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(236c)

Compound 236b was prepared from(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (236a) (72 g,307 mmol) and 3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesiumbromide (52c) (430 mL, 430 mmol) as described in step-2 of scheme-222for preparation of compounds 222d and 222c to afforded mixture ofdiastereoisomers 236b and 236c. The crude mixture was purified by flashcolumn chromatography [silica gel 4.5 kg, eluting with ethyl acetate inhexanes from 0-60%] to afford;

-   -   1.        (R)—N—((R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide        (236b) (47.32 g, 45% yield) isolated as an off-white solid; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.83 (t, J=1.6 Hz, 1H), 7.76-7.64 (m,        2H), 7.54 (t, J=7.7 Hz, 1H), 6.93 (dd, J=11.4, 8.3 Hz, 1H), 6.73        (dd, J=8.8, 2.2 Hz, 1H), 6.57 (ddd, J=8.4, 4.4, 2.2 Hz, 1H),        6.01 (d, J=6.0 Hz, 1H), 5.48 (d, J=6.0 Hz, 1H), 5.15 (s, 2H),        1.13 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −136.86; MS (ES⁺): MS        (ES+) 346.3 (M+1), 368.3 (M+Na); MS (ES−) 725.3 (M+Cl); Chiral        HPLC method: Column AD-H; Solvent 90:10:1.0        (hexane/isopropanol/TEA), 25° C., 1.0 ml/min, UV=260 nm;        R_(t)=26.207 (peak-1 for compound 236b) >99.99% ee; Optical        rotation: [α]_(D)=(−) 52.31 [0.845, MeOH]; Analysis calculated        for C₁₈H₂₀FN₃OS: C, 62.59; H, 5.84; N, 12.16; Found: C, 62.44;        H, 5.90; N, 11.93.    -   2.        (R)—N—((S)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide        (236c) (13.51 g, 13% yield) as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 7.88 (t, J=1.7 Hz, 1H), 7.77-7.65 (m, 2H), 7.54 (t,        J=7.7 Hz, 1H), 6.92 (dd, J=11.5, 8.3 Hz, 1H), 6.69 (dd, J=8.9,        2.2 Hz, 1H), 6.50 (ddd, J=8.4, 4.4, 2.2 Hz, 1H), 6.07 (d, J=6.5        Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 5.15 (s, 2H), 1.15 (s, 9H); ¹⁹F        NMR (282 MHz, DMSO-d₆) δ −136.88; MS (ES⁺): MS (ES+) 346.3        (M+1), 368.2 (M+Na), MS (ES−) 344.2 (M−1); HPLC: Chiral HPLC        method: Column AD-H; Solvent 90:10:1.0 (hexane/isopropanol/TEA),        25° C., 1.0 ml/min, UV=260 nm; R_(t)=26.497 (peak-1 for compound        236b, 2.5953%), R_(t)=28.253 (peak-2 for compound 236c,        97.4047%); 94.8094% ee. Optical rotation: [α]_(D)=(−) 77.82        [1.19, MeOH]; Analysis calculated for C₁₈H₂₀FN₃OS: C, 62.59; H,        5.84; N, 12.16; S, 9.28. Found: C, 62.58; H, 5.71; N, 12.15; S,        9.20.

Step-3: Preparation of(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d)

Compound (236d) was prepared from(R)—N—((R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(236b) according to the procedure reported in step-3 of scheme-222 asdescribed for preparation of compound 222d gave(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d)hydrochloride salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.39-9.10 (m, 3H), 7.57-7.49 (m, 2H), 7.45-7.34 (m, 3H), 7.26 (d, J=5.8Hz, 1H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 5.58 (d, J=5.5 Hz, 1H); ¹⁹F NMR(282 MHz, DMSO) δ −129.75; MS (ES−) 240.2 (M−1). The above solid wasdissolved in water, basified by addition of NaOH (3 N). extracted withethyl acetate. The organic layer was washed with brine, dried, filteredand concentrated in vacuum to furnish(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d) free baseas a brown oil; ¹H NMR (300 MHz, DMSO-d6) 1H NMR (300 MHz, DMSO-DMSO-d₆)δ 7.84 (t, J=1.7 Hz, 1H), 7.66 (ddt, J=7.7, 6.2, 1.4 Hz, 2H), 7.48 (t,J=7.7 Hz, 1H), 6.88 (dd, J=11.5, 8.3 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz,1H), 6.55 (ddd, J=8.4, 4.5, 2.2 Hz, 1H), 5.06 (s, 2H), 5.00 (s, 1H),2.27 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −138.23; 19F NMR (282 MHz,DMSO-d₆) δ −137.59; Chiral HPLC purity 99.8838% ee; MS (ES−) 240.3(M−1), 276.1 (M+Cl); Optical rotation: [α]_(D)=(+) 27.99 [1.665, MeOH].

Step-4: Preparation of(+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)benzonitrile(236e) and (+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile (236f)

To a stirred solution of(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d) (8.321 g,34.5 mmol) free base in MeOH (20 mL) was addedcyclopropanecarboxaldehyde (3.25 mL, 43.1 mmol) at 0° C. and stirred for30 mins. To this sodium borohydride (2.61 g, 69.0 mmol) was added andstirred at 0° C. for 1 hr. The reaction was concentrated in vacuum toremove methanol and residue was dissolved in ethyl acetate (200 mL),washed with water (2×50 mL), brine (50 mL), dried and concentrated. Thecrude residue was purified by flash column chromatography (silica gel120 g, eluting with ethyl acetate in hexanes 0-100%) to afford

-   -   1.        (+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)benzonitrile        (236e) (1.087 g, 3.11 mmol, 9.02% yield) as a colorless syrup;        ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (t, J=1.7 Hz, 1H), 7.75 (dt,        J=7.9, 1.5 Hz, 1H), 7.64 (dt, J=7.7, 1.4 Hz, 1H), 7.48 (t, J=7.7        Hz, 1H), 6.90 (dd, J=11.9, 8.2 Hz, 1H), 6.84 (dd, J=8.9, 2.1 Hz,        1H), 6.57 (ddd, J=8.2, 4.5, 2.0 Hz, 1H), 5.34 (td, J=6.0, 2.4        Hz, 1H), 4.81 (d, J=4.2 Hz, 1H), 2.96 (t, J=6.3 Hz, 2H), 2.59        (m, 1H), 2.27 (m, 2H), 1.03 (m, 1H), 0.98-0.84 (m, 1H), 0.40 (m,        4H), 0.26-0.17 (m, 2H), 0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −137.04; MS (ES−) 348.4 (M−1); Optical rotation: [α]_(D)=(+)        17.96 [0.245, MeOH].    -   2.        (+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile        (236f) (7.891 g, 26.7 mmol, 77% yield) as colorless syrup; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.84 (t, J=1.6 Hz, 1H), 7.71 (dt,        J=7.9, 1.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.49 (t, J=7.7 Hz, 1H),        6.88 (dd, J=11.5, 8.3 Hz, 1H), 6.81 (dd, J=9.0, 2.2 Hz, 1H),        6.56 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.08 (s, 2H), 4.76 (d, J=2.8        Hz, 1H), 2.48 (m, 1H), 2.26 (m, 2H), 0.91 (m, 1H), 0.42-0.34 (m,        2H), 0.09-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.18; MS        (ES+) 296.3 (M+1), (ES−) 294.3 (M−1); Optical rotation:        [α]_(D)=(+) 22.05 [0.88, CHCl₃].

Step-5: Preparation of1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (236g)

To a stirred solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(1.0 g, 3.55 mmol) in THF (10 mL) was added LiHMDS (14 mL, 1M in THF)and heated at reflux overnight. The reaction mixture was cooled to roomtemperature and pH was adjusted to 2-3 using KHSO₄ (1N aqueoussolution). The organic solvent was removed under vacuum and the aqueouslayer was extracted with EtOAc (5×50 mL). The organic layers werecombined dried over MgSO₄, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silicagel, eluting with CMA-80 in chloroform 0-100%, followed by 0-100%chloroform in CMA 50) to give1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(236g) (250 mg, 23%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.63-8.88 (m, 4H), 8.03-7.92 (m, 2H), 7.87 (dt, J=8.1, 1.3 Hz, 1H),7.74 (t, J=7.9 Hz, 1H), 7.03 (d, J=0.6 Hz, 1H); MS (ES+) 299.3 (M+1);297.3 (M−1).

Step-6: Preparation of(+)-1-(3-carbamimidoylphenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(236h)

To a solution of1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid hydrochloride (236g) (200 mg, 0.671 mmol) in DMF (10 mL) was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop, 375 mg,0.805 mmol), pyridine (265 mg, 3.35 mmol), and stirred at roomtemperature for 10 min. To the reaction mixture was added(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile(236f) (198 mg, 0.671 mmol) and stirred at room temperature overnightunder nitrogen atmosphere. The reaction was quenched with aqueous HCl (6N, 20 mL) and washed with ethyl acetate (4×50 mL). The aqueous layer wasbasified to pH 9 using 1 N NaOH and extracted with ethyl acetate (4×40mL). The organic layers were combined dried, filtered, and concentratedin vacuum to dryness. The residue obtained was purified by flash columnchromatography (silica gel, eluting with 0-100% CMA-80 in chloroform) tofurnish compound 236h as a free base. The free base was dissolved indioxane (5 mL) added HCl (4N in dioxane, 4 mL) and stirred at roomtemperature for 1 h. The solution was concentrated and dried undervacuum to(+)-1-(3-carbamimidoylphenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(236h) (74 mg, 0.129 mmol, 19.17% yield) salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.87 (s, 1H), 10.43 (s, 2H), 9.51 (s, 2H), 9.31(s, 2H), 8.28 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H),8.01-7.69 (m, 6H), 7.65 (t, J=7.8 Hz, 1H), 7.41 (t, J=9.4 Hz, 1H),5.97-5.59 (m, 1H), 2.80-2.60 (m, 2H), 1.32-1.01 (m, 2H), 0.99-0.72 (m,1H), 0.66-0.43 (m, 2H), 0.41-0.16 (m, 2H); MS (ES⁺): MS (ES+) 576.4(M+1); Optical rotation: [α]_(D)=(+) 2.31 [0.26, MeOH].

Preparation of(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(237a)

To a solution of1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (236g) (300 mg, 1.006 mmol) in DMF (10 mL) was addedbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrop, 563 mg,1.207 mmol), pyridine (398 mg, 5.03 mmol) stirred at room temperaturefor 10 min and added((R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (416 mg, 1.006 mmol). The reaction mixture was stirred at roomtemperature overnight, quenched with aqueous HCl (6 N, 20 mL) and washedwith ethyl acetate (4×30 mL). The aqueous layer was basified to pH 9using 1 N NaOH and extracted with ethyl acetate (4×40 mL). The organiclayers were combined dried, filtered, and concentrated in vacuum todryness. The residue obtained was purified by flash columnchromatography (silica gel, eluting with 0-100% CMA-80 in chloroform) tofurnish 237a free base a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 9.64-9.38 (m, 2H), 9.22 (s, 2H), 8.01 (m, 1H), 7.95 (m, 1H),7.92-7.85 (m, 2H), 7.79-7.64 (m, 4H), 7.54 (m, 2H), 7.37-7.16 (m, 2H),2.39-2.19 (m, 2H), 1.15-0.90 (m, 2H), 0.72-0.55 (m, 1H), 0.41-0.28 (m,2H), −0.01-−0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.84, −123.70; MS(ES+) 590.5 (M+1); IR (KBr) 2235 cm⁻¹; Optical rotation: [α]_(D)=(+)6.53 (0.245, methanol); The free base was dissolved in dioxane (5 mL)added HCl (4 N in dioxane, 10 eq) and stirred at room temperature for 1h. The solution was concentrated and dried under vacuum to affordfurnish(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(237a) (60 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s,1H), 9.54 (s, 5H), 9.33 (s, 3H), 8.12-7.06 (m, 12H), 3.77-3.58 (m, 2H),2.74-2.21 (m, 2H), 0.78-0.51 (m, 1H), 0.47-0.22 (m, 2H), −0.00 (s, 2H);¹⁹F NMR (282 MHz, DMSO) δ −60.84, −123.62; MS (ES+) 590.5 (M+1), (ES−)624.5 (M+Cl); IR (KBr) 2232 cm¹.

Preparation of1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c) Step-1: Preparation of1-(3-cyanophenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238a)

Compound 238a was prepared from1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(209b) (3 g, 7.70 mmol) according to the procedure reported in step-3 ofscheme 208 to afford after flash column chromatography [silica gel 80 g,eluting with 0-50% ethyl acetate/methanol (9:1) in hexanes]1-(3-cyanophenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238a) (3.518 g, 69.9% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.55-8.45 (m, 1H), 8.40 (td, J=5.0, 1.5 Hz, 2H), 10.58 (s,1H), 8.11 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.92-7.85 (m,1H), 7.75-7.67 (m, 3H), 7.55 (d, J=7.0 Hz, 1H), 7.39-7.18 (m, 3H), 5.57(s, 1H), 2.70-2.50 (m, 2H), 1.12 (s, 9H), 0.98-0.78 (m, 1H), 0.73-0.51(m, 1H), 0.35 (m, 2H), −0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.78,−122.81; MS (ES+) 653.5 (M+1); (ES−) 651.5 (M−1); Optical Rotation[α]_(D)=(−) 21.82 [0.55, MeOH].

Step-2: Preparation of1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c)

To a solution of1-(3-cyanophenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238a) (490 mg, 0.751 mmol) in ethanol (50 mL) was added hydroxylamine(124 mg, 3.75 mmol) and heated at reflux overnight. The reaction wascooled to room temperature and concentrated in vacuum to dryness. Theresidue ofN-(5-(3-cyclopropyl-1-((−)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238b) was dissolved in acetic acid (50 mL) and added Ac₂O (10 mL). Thereaction mixture was stirred at room temperature for 2 h, added Pd/C(200 mg) and hydrogenated at 65 psi for 12 h at room temperature. Thereaction mixture was filtered through a Celite Pad and filtrate wasconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel, 12g eluting with CMA80/CHCl₃, 0-100%)to furnish1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c) (256 mg, 0.382 mmol, 50.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.78 (s, 4H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (dd, J=4.8,1.5 Hz, 1H), 8.01-7.96 (m, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.81-7.74 (m,1H), 7.73-7.62 (m, 3H), 7.59-7.53 (m, 1H), 7.37-7.18 (m, 3H), 5.55 (s,1H), 2.76-2.54 (m, 2H), 1.12 (s, 9H), 0.92 (m, 2H), 0.63 (m, 1H), 0.34(m, 2H), −0.09 (m, 2H). ¹⁹F NMR (282 MHz, DMSO) δ −60.65, −122.63; MS(ES+) 670.5 (M+1), (ES−) 668.5 (M−1); Optical Rotation [α]_(D)=(−) 63.85[0.26, MeOH].

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238d)

To a solution of1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c) (100 mg, 0.149 mmol) in MeOH (5 mL) was added HCl (0.070 mL,0.280 mmol, 4 N in 1,4-dioxane) and stirred at room temperature for 2 h.Additional HCl (4 N in 1,4-dioxane, 0.12 mL) was added and continuedstirring until reaction was complete. The reaction mixture wasconcentrated to dryness and purified twice by flash columnchromatography [silica gel, eluting with chloroform/CMA80 (1:0 to 0:1)]to afford compound 238d (30 mg, 0.053 mmol, 35.5%) free base as an oil.The free base (30 mg, 0.053 mmol) was dissolved in methanol (8 mL) added4 N HCl (aq. 0.053 mL) and concentrated in vacuum to furnish(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238d) (35 mg, 92.8%) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.58 (s, 3H), 9.52 (s, 3H), 9.27 (s, 2H),8.70-8.60 (m, 2H), 8.06-7.93 (m, 3H), 7.92-7.85 (m, 1H), 7.80 (s, 1H),7.76 (m, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.47-7.32 (m, 2H), 2.75-2.40(m, 2H), 1.12 (m, 2H), 0.77-0.57 (m, 1H), 0.44-0.30 (m, 2H), 0.08 to−0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.50, −119.76; MS (ES−):564.5 (M−1); Optical Rotation [α]_(D)=(+) 2.22 [0.18, MeOH].

Preparation of:(+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(239c) Step 1: Preparation of4-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)benzamide(239a)

To a solution of(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (1.41 g, 3.41 mmol) in ethanol (80 mL) was added conc. NH₄OH (30mL) hydrogen peroxide (1.200 mL, 13.59 mmol) and stirred at roomtemperature for 22 h. The reaction mixture was concentrated in vacuum todryness and purified by flash column chromatography [silica gel withchloroform/methanol (1:0 to 9:1)] to afford4-((−)-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)benzamide(239a) (335 mg, 22.77%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.93 (s, 1H), 7.82-7.72 (m, 2H), 7.43-7.36 (m, 2H), 7.33 (s, 1H), 6.88(dd, J=11.2, 8.5 Hz, 1H), 6.70 (dd, J=8.8, 2.3 Hz, 1H), 6.48 (ddd,J=8.5, 4.2, 2.3 Hz, 1H), 5.14-4.98 (m, 3H), 2.65-2.40 (m, 2H), 1.20-1.05(m, 1H), 1.13 (s, 9H), 0.97-0.80 (m, 1H), 0.72-0.55 (m, 1H), 0.42-0.29(m, 2H), 0.07-−0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.75; MS(ES+): 432.4 (M+1); Optical rotation: [α]_(D)=(−) 77.82 [0.275, MeOH].

Step 2: Preparation of tert-butyl3-(5-(5-((−)-1-(4-carbamoylphenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-cyano-1H-pyrazol-1-yl)benzylcarbamate(239b)

Compound 239b was prepared from4-((−)-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)benzamide(239a) (275 mg, 0.636 mmol) and1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylicacid (234b) (240 mg, 0.7 mmol) using procedure as reported in step-3 ofscheme-208 gave after purification by flash column chromatography[silica gel with chloroform/methanol (1:0 to 19:1)] tert-butyl3-(5-(5-((−)-1-(4-carbamoylphenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-cyano-1H-pyrazol-1-yl)benzylcarbamate(239b) (188 mg, 39.1%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 10.62 (s, 1H), 7.93 (s, 1H), 7.81-7.70 (m, 3H), 7.61-7.14 (m, 11H),5.39 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.60-2.40 (m, 2H), 1.38 (s, 9H),1.12 (s, 9H), 1.18-1.02 (m, 1H), 0.98-0.78 (m, 1H), 0.72-0.55 (m, 1H),0.40-0.25 (m, 2H), 0.08 to −0.20 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.20; MS (ES+): 756.6 (M+1); Optical rotation: [α]_(D)=(−) 62.04[0.245, MeOH].

Step 3:(+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(239c)

To a solution of tert-butyl3-(5-(5-((−)-1-(4-carbamoylphenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-cyano-1H-pyrazol-1-yl)benzylcarbamate(239b) (161 mg, 0.213 mmol) in ethanol (15 mL) was added conc. HCl(0.180 mL, 2.162 mmol) heated at reflux for 1 h, cooled to roomtemperature and concentrated in vacuum to dryness. The residue waspurified twice by column chromatography [silica gel, eluting withchloroform/CMA80 (1:0 to 2:1) for first column and chloroform/methanol(1:0 to 3:1) for second column] to afford 239c (50 mg, 33.7%) free baseas a white solid. The free base (46 mg, 0.083 mmol) was dissolved inethanol (5 mL) added conc. HCl (aqueous 0.035 mL) and concentrated invacuum to dryness. The residue was dissolved in 5 mL of water andconcentrated to give(+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-cyano-1H-pyrazole-5-carboxamide(239c) (58 mg, 91.85%) hydrochloride salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.25 (s, 3H), 8.36 (s, 3H), 8.06 (s, 1H),7.91 (d, J=8.2 Hz, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.64-7.25 (m, 9H),4.12 (q, J=5.9 Hz, 2H), 2.70-2.40 (m, 2H), 1.20-0.95 (m, 2H), 0.75-0.60(m, 1H), 0.49-0.28 (m, 2H), 0.03-0.06 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −120.45; MS (ES+): 574.5 (M+Na); Optical rotation:[α]_(D)=(+) 12.5 [0.24, MeOH].

Preparation of:(−)-1-(3-(aminomethyl)phenyl)-3-cyano-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-5-carboxamide(240b) Step 1: Preparation of tert-butyl3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(240a)

Compound 240a was prepared from(−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f)(147 mg, 0.545 mmol) and1-(3-((tert-butoxycarbonylamino)methyl)-phenyl)-3-cyano-1H-pyrazole-5-carboxylicacid (234b) (205 mg, 0.6 mmol) using procedure as reported in step-3 ofscheme-208 to afford after purification by flash column chromatography[silica gel with chloroform/methanol (1:0 to 19:1)] tert-butyl3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(240a) (161 mg, 49.6%) as a yellow gum. ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H), 7.73 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.53-7.12 (m, 12H),4.83 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.32-2.20 (m, 2H), 1.38 (s, 9H),0.97-0.83 (m, 1H), 0.44-0.29 (m, 2H), 0.08 to −0.08 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −123.61; MS (ES+): 595.5 (M+1).

Step 2: Preparation of(−)-1-(3-(aminomethyl)phenyl)-3-cyano-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-5-carboxamide(240b)

To a solution of tert-butyl3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate(240a) (150 mg, 0.252 mmol) in ethanol (15 mL) was added conc. HCl(0.210 mL, 2.52 mmol) heated at reflux for 1 h, cooled to roomtemperature and concentrated in vacuum to dryness. The residue waspurified twice by column chromatography [silica gel, eluting withchloroform/CMA80 (1:0 to 2:1) for first column and chloroform/methanol(1:0 to 9:1) for second column] to afford(−)-1-(3-(aminomethyl)phenyl)-3-cyano-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-5-carboxamide(240b) (44 mg, 35.3%) free base as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 7.71 (s, 1H), 7.65-7.12 (m, 12H), 4.83 (s, 1H), 3.77 (s, 2H),2.26 (m, 2H), 0.90 (s, 1H), 0.44-0.29 (m, 2H), 0.12-−0.06 (m, 2H);(ES+): 517.5 (M+Na); IR 2244 cm⁻¹; Optical rotation: [α]_(D)=(−) 7.62[0.105, CH₃OH].

Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(241a)

Compound 241a was prepared from1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid hydrochloride (236g) (500 mg, 1.677 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (693 mg, 1.677 mmol) according to procedure described inscheme-237 for preparation of compound 237a gave after purification byflash column chromatography (silica gel, eluting with 0-100% CMA-80 inchloroform) compound 241a (235 mg, 0.399 mmol, 23.77% yield) free baseas a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s, 4H), 8.26 (s,1H), 8.20 (d, J=7.7 Hz, 1H), 8.04-7.81 (m, 8H), 7.55 (m, 1H), 7.45 (t,J=9.4 Hz, 1H), 2.60 (s, 2H), 2.55-2.45 (m, 2H), 1.42-1.19 (m, 2H), 0.90(m, 1H), 0.70-0.46 (m, 2H), 0.19 (m, 2H). The free base was dissolved indioxane (5 mL) added HCl (4N in dioxane, 0.4 mL) and stirred at roomtemperature for 1 h. The solution was concentrated and dried undervacuum to afford(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(241a) hydrochloride salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.77 (s, 1H), 9.50 (s, 3H), 9.22 (s, 2H), 8.10-7.68 (m, 7H), 7.54 (t,J=7.6 Hz, 3H), 7.33 (s, 2H), 1.20-0.94 (m, 2H), 0.71-0.57 (m, 1H), 0.36(d, J=7.4 Hz, 2H), −0.00-−0.14 (m, 2H); MS (ES+): 590.5 (M+1); IR (KBr)2233 cm⁻¹; optical rotation (+) 14.81 (0.27, methanol).

Preparation of (−)-ethyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242c) Step-1: Preparation of ethyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242a)

Compound 242a was prepared from1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c) (109 mg, 0.163 mmol) and ethyl carbonochloridate (0.016 mL, 0.163mmol) according to the procedure reported for preparation of compound233a in scheme-233 to furnish after purification by flash columnchromatography [silica gel eluting with hexanes/10% methanol in ethylacetate (1:0 to 1:1)] ethyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242a) (50 mg, 0.067 mmol, 41.4%) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.59 (s, 1H), 9.20 (s, 2H), 8.51-8.47 (m, 1H), 8.41 (dd,J=4.7, 1.5 Hz, 1H), 8.15 (t, J=1.9 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H),7.74-7.53 (m, 5H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 7.28-7.16 (m, 2H), 5.55(s, 1H), 4.06 (q, J=7.1 Hz, 2H), 2.75-2.40 (m, 2H), 1.20-1.00 (m, 1H),1.21 (t, J=7.1 Hz, 3H), 1.11 (s, 9H), 0.97-0.81 (m, 1H), 0.70-0.52 (m,1H), 0.40-0.22 (m, 2H), −0.02 to −0.18 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.62, −122.82; MS (ES+): 742.6 (M+1); Optical rotation:[α]_(D)=(−) 68.09 [0.235, MeOH].

Step-2: Preparation of (−)-ethyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242c)

To a solution of ethyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242a) (48 mg, 0.065 mmol) in MeOH (5 mL) was added HCl (0.065 mL, 0.259mmol, 4 N in 1,4-dioxane) stirred at room temperature and concentratedin vacuum to dryness. The residue was purified by flash columnchromatography [silica gel, eluting with chloroform/CMA80 (1:0 to 2:1)]to afford compound 242c (24 mg, 0.038 mmol) free base as a white syrup.The free base was dissolved in methanol (8 mL) added 4 N HCl (aq. 0.038mL) and concentrated in vacuum to dryness to afford (−)-ethyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242c) (38 mg) hydrochloride as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 11.44 (s, 1H), 10.88 (s, 1H), 10.60 (s, 1H), 9.61 (s, 3H), 8.73-8.56(m, 2H), 8.06-7.85 (m, 4H), 7.80 (s, 1H), 7.73 (m, 1H), 7.64 (m, 1H),7.57-7.51 (m, 1H), 7.46-7.36 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 2.65-2.40(m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.13 (m, 2H), 0.75-0.60 (m, 1H), 0.37(m, 2H), 0.05 to −0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.71,−119.86; MS (ES+): 638.5 (M+1); Optical rotation: [α]_(D)=(−) 9.78[0.225, MeOH].

Preparation of (−)-hexyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242d) Step-1: Preparation of hexyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242b)

Compound 242b was prepared from1-(3-carbamimidoylphenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238c) (80 mg, 0.119 mmol) and hexyl chloroformate (19.7 mg, 0.119 mmol)according to the procedure reported for preparation of compound 233b inscheme-233 to furnish after purification by flash column chromatography(silica gel, 12g, eluting with CMA80/CHCl₃, 0-60%) hexyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242b) (88 mg, 92.68% yield) as an off white solid; ¹H NMR (300 MHz,CDCl₃) δ 8.54 (s, 3H), 8.33-8.15 (m, 1H), 8.16-7.88 (m, 2H), 7.86-7.62(m, 2H), 7.20-6.99 (m, 2H), 4.24 (td, J=7.0, 5.1 Hz, 2H), 4.17 (d, J=8.7Hz, 1H), 2.74 (m, 2H), 1.87-1.69 (m, 2H), 1.50-1.22 (m, 16H), 1.07-0.92(m, 6H), 0.80-0.63 (m, 1H), 0.47 (m, 2H), −0.00 (m, 2H); ¹⁹F NMR (282MHz, CDCl3) δ −62.20, −129.62; MS (ES⁺): MS (ES+) 798.6 (M+1); Opticalrotation: [α]_(D)=(−) 59.59 [0.245, CH₃OH].

Step-2: Preparation of (−)-hexyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242d)

To a solution of hexyl(3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242b) (70.0 mg, 0.09 mmol) in anhydrous dioxane (3.0 mL) at roomtemperature was added HCl (0.1 mL, 4N in dioxane). The resulting mixturewas stirred for 1 h and concentrated in vacuum. The residue obtained waspurified twice by flash column chromatography (silica gel, first column(12g) eluting with CMA-80 in CHCl₃ 0-100%, second column (4g) MeOH inchloroform 0-40%) to furnish 242b as a free base. The free base wasdissolved in MTBE (4 mL), added HCl (4N HCl in dioxane, 0.5 mL) andstirred for 30 min at room temperature. The slurry was concentrated invacuum and dried to furnish (−)-hexyl(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(242d) (45 mg, 74%) as an off white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.87 (s, 1H), 10.59 (s, 1H),9.60 (s, 3H), 8.66 (m, 2H), 8.06-7.96 (m, 3H), 7.95-7.86 (m, 2H), 7.80(m, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.58-7.50 (m, 1H), 7.41 (m, 2H),4.27 (m, 2H), 2.56 (m, 2H), 1.67 (m, 2H), 1.44-1.21 (m, 8H), 1.20-1.03(m, 3H), 0.68 (s, 1H), 0.49-0.31 (m, 2H), 0.00 (m, 2H); ¹⁹F NMR (282MHz, DMSO) δ −60.63, −119.82; MS (ES+) 694.6 (M+1); Optical rotation:[α]_(D)=(−) 10.0 [0.26, MeOH].

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(243a)

Compound 243a was prepared from1-(3-cyanophenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(238a) (40 mg, 0.061 mmol) according to the procedure reported forpreparation of compound 15g in step-6 of scheme-15 to furnish afterpurification by flash column chromatography [silica gel withchloroform/methanol (1:0 to 9:1)]1-(3-(aminomethyl)phenyl)-N-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(243a) (13 mg, 32.3%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz, 1H),7.69 (d, J=8.1 Hz, 1H), 7.62-7.18 (m, 9H), 5.57 (s, 1H), 3.77 (s, 2H),2.75-2.40 (m, 2H), 1.20-1.00 (m, 1H), 1.12 (s, 9H), 0.98-0.79 (m, 1H),0.70-0.55 (m, 1H), 0.40-0.28 (m, 2H), 0.02-−0.20 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.54, −122.96; MS (ES+): 679.7 (M+Na); OpticalRotation [α]_(D)=(−) 81.90 [0.105, MeOH].

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244g) Step-1: Preparation of (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a)

To a stirred solution of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(209c) (1.603 g, 2.118 mmol) in methanol (18 mL) cooled to 0° C. wasadded 4 N hydrochloric acid in dioxane (1.60 mL, 6.40 mmol) and stirredat 0° C. for 2.5 h. The reaction mixture was quenched with triethylamine(1.10 mL, 7.89 mmol) and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography [silica gel,eluting with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] tofurnish (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (658 mg, 47.6%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 8.46-8.38 (m, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.71-7.60 (m,2H), 7.59-7.32 (m, 8H), 7.25 (t, J=9.5 Hz, 1H), 4.29-4.19 (m, 2H), 2.42(s, 2H), 2.37-2.22 (m, 2H), 1.44 (s, 9H), 1.19-1.02 (m, 2H), 0.78-0.61(m, 1H), 0.50-0.34 (m, 2H), 0.04-−0.06 (m, 2H); 19F NMR (282 MHz, DMSO)δ −60.60, −123.99; MS (ES+) 653.3 (M+1), (ES−) 651.5 (M−1); Opticalrotation: [α]_(D)=(−) 1.45 [0.275, CH₃OH].

Step-2: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244b)

To a solution of (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (132 mg, 0.202 mmol) in pyridine (5 mL) was addedN,N-dimethylpyridin-4-amine (30.0 mg, 0.246 mmol), pivaloyl chloride(0.030 mL, 0.243 mmol) and stirred at room temperature for 5 h.Additional pivaloyl chloride (0.060 mL) was added and stirred at roomtemperature for 22 h. Additional pivaloyl chloride (0.060 mL) was addedand heated at 70° C. for 15 h. The reaction mixture was cooled to roomtemperature, quenched with methanol (5 mL) and concentrated in vacuum todryness. The residue was diluted with ethyl acetate (150 mL), washedwith water (75 mL), brine (75 mL), dried over MgSO₄, filtered andconcentrated in vacuum to dryness. The residue was purified by flashcolumn chromatography [silica gel with chloroform/methanol (1:0 to19:1)] to furnish tert-butyl3-(5-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244b) (29 mg, 19.5%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.58 (s, 1H), 8.49 (s, 1H), 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.67-7.16 (m,12H), 4.18 (d, J=6.2 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s, 9H), 1.11 (s,9H), 1.00-0.80 (m, 2H), 0.70-0.55 (m, 1H), 0.40-0.27 (m, 2H), −0.05 to−0.20 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.60, −123.86; MS (ES+)759.7 (M+Na).

Step-3: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244g)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244b) (26 mg, 0.035 mmol) in ethanol (6 mL) was added conc. HCl (0.030mL, 0.360 mmol) and heated at reflux for 1 h. The solution was cooled toroom temperature and concentrated in vacuum to dryness to give(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244g) (24 mg, 0.034 mmol, 96%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.69 (s, 1H), 8.65-8.58 (s, 2H), 8.33 (s, 3H), 8.11 (s, 1H),7.75-7.45 (m, 8H), 7.32-7.18 (m, 2H), 4.12 (q, J=5.8 Hz, 2H), 2.65-2.40(m, 2H), 1.11 (s, 9H), 1.02-0.84 (m, 2H), 0.70-0.56 (m, 1H), 0.40-0.28(m, 2H), −0.06 to −0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.62,−123.06; MS (ES+): 637.5 (M+1); Optical rotation: [α]_(D)=(−) 0.39[1.55, CH₃OH].

Preparation of(−)-N-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244h) Step-1: Preparation of tert-butyl3-(5-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244c)

To a solution of (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (170 mg, 0.260 mmol) in pyridine (5 mL) was addedN,N-dimethylpyridin-4-amine (38.0 mg, 0.311 mmol), acetic anhydride(0.030 mL, 0.313 mmol) and stirred at room temperature for 5 h.Additional acetic anhydride (0.060 mL) was added and stirred at roomtemperature for 22 h. Additional acetic anhydride (0.060 mL) was addedand stirred at room temperature for 15 h. The reaction was quenched withmethanol (5 mL) and concentrated in vacuum to dryness. The residue wasdiluted with ethyl acetate (150 mL), washed with water (75 mL), brine(75 mL), dried over MgSO₄, filtered and concentrated in vacuum todryness. The residue was purified by flash column chromatography [silicagel with chloroform/methanol (1:0 to 19:1)] to afford tert-butyl3-(5-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244c) (53 mg, 29.3%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.59 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.8, 1.5 Hz, 1H),8.31 (s, 1H), 7.69-7.17 (m, 11H), 4.19 (d, J=6.2 Hz, 2H), 2.65-02.40 (m,2H), 1.89 (s, 3H), 1.38 (s, 9H), 1.05-0.80 (m, 2H), 0.70-0.50 (m, 1H),0.40-0.25 (m, 2H), −0.05 to −0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.62, −123.29; MS (ES−): 693.6 (M−1).

Step-2: preparation of(−)-N-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244h)

Compound 244h was prepared from tert-butyl3-(5-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244c) (45 mg, 0.065 mmol) and conc. HCl (0.054 mL, 0.648 mmol) usingthe procedure as described for preparation of compound 244g in step-3 ofscheme-244 to afford(−)-N-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244h) (44 mg) hydrochloride salt as an off-white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.72 (s, 1H), 8.70-8.62 (m, 2H), 8.55 (s, 1H), 8.39(bs, 3H), 8.22 (d, J=8.2 Hz, 1H), 7.83-7.21 (m, 9H), 4.12 (q, J=5.7 Hz,2H), 2.60-2.40 (m, 2H), 1.91 (s, 3H), 1.11-0.77 (m, 2H), 0.70-−0.54 (m,1H), 0.41-0.23 (m, 2H), −0.04 to −0.12 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.63, −122.26; MS (ES+): 595.4 (M+1); Optical rotation:[α]_(D)=(−) 1.51 [0.265, CH₃OH].

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244i) Step-1: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244d)

To a solution of (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (175 mg, 0.27 mmol) in anhydrous pyridine/THF (10 mL, 1:1, v/v)was added DMAP (33.0 mg, 0.27 mmol), followed by addition of isobutyrylchloride (142.8 mg, 1.34 mmol, 5.0 eq) in anhydrous THF (2.0 mL). Theresulting reaction mixture was stirred for 11 h at room temperature andconcentrated in vacuum to dryness. The residue was dissolved in EtOAc(100 mL), washed with water (2×50 mL), brine, dried over MgSO₄, filteredand concentrated. The residue obtained was purified by flash columnchromatography (silica gel, 12g, eluting with EtOAc/MeOH (9:1) and hex,0-50%) to furnish tert-butyl3-(5-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244d) (150 mg, 78.47% yield) as a white solid; ¹H NMR (300 MHz, CD₃OD)δ 8.52 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.9, 1.5 Hz, 1H), 7.81 (dt, J=7.8,2.2 Hz, 2H), 7.48-7.29 (m, 5H), 7.26-7.10 (m, 3H), 4.29 (s, 2H),2.74-2.53 (m, 2H), 2.28 (q, J=7.6 Hz, 2H), 1.43 (s, 9H), 1.05 (m, 3H),0.95-0.82 (m, 2H), 0.69-0.61 (m, 1H), 0.42-0.34 (m, 2H), −0.03-−0.12 (m,2H); MS (ES+) 709.5 (M+1).

Step-2: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244i)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244d) (150 mg, 0.211 mmol) in ethanol (20 mL) was added HCl (4N indioxane, 0.35 mL, 10 eq) and heated at reflux for 2 h. The reaction wasconcentrated in vacuum and the residue obtained was purified by flashcolumn chromatography (silica gel 12 g, eluting with CHCl₃ in CMA-800-60%) to furnish compound 244i (71 mg) free base as a white solid. Thefree base was dissolved in methanol (5 mL), added HCl (0.2 mL, 4N indioxane) at room temperature and concentrated in vacuum to dryness. Theresidue was dissolved in water (2 mL) and two drops of acetonitrile,lyophilized to furnish(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244i) (72 mg, 84%) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.80-8.66 (bs, 2H), 8.60 (bs, 3H), 8.39(d, J=8.1 Hz, 1H), 7.91 (m, 1H), 7.73 (m, 2H), 7.65 (d, J=7.2 Hz, 1H),7.59-7.48 (m, 4H), 7.35-7.20 (m, 3H), 4.10 (d, J=5.8 Hz, 2H), 2.54 (m,2H), 2.24 (q, J=7.4 Hz, 2H), 0.92 (m, 5H), 0.70-0.55 (m, 1H), 0.33 (m,2H), −0.07 (m, 2H); 19F NMR (282 MHz, DMSO) δ −60.77, −122.21; MS (ES⁺):MS (ES+) 609.5 (M+1); Optical rotation: [α]_(D)=(−) 1.57 [0.255, CH₃OH].

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244j) Step-1: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244e)

Compound 244e was prepared from (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (175 mg, 0.27 mmol) and isobutyryl chloride (142.8 mg, 1.34 mmol,5.0 eq) using the procedure as described for preparation of compound244d in scheme-244 to furnish after purification by flash columnchromatography [silica gel, 12g column, eluting with EtOAc/MeOH (9:1)and hexane 0-50%] tert-butyl3-(5-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244e) (150 mg, 76.86% yield) as a white solid; MS (ES+) 723.5 (M+1);(ES−) 721.5 (M−1).

Step-2: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244j)

Free base of compound 244j was prepared from tert-butyl3-(5-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244e) (150 mg, 0.208 mmol) and HCl (4N in dioxane, 0.35 mL, 10 eq)using the procedure as described for preparation of free base ofcompound 244i in scheme-244 to afford after purification by flash columnchromatography (silica gel 12 g, eluting with CHCl₃ in CMA-80 0-60%)compound 244j (63 mg) free base as a white solid. The free base wasconverted to hydrochloride salt as described in preparation ofhydrochloride salt of compound 244i from its free base in scheme-244 toafford(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244j) (64 mg) hydrochloride salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.75 (s, 1H), 8.68 (m, 2H), 8.48 (m, 3H), 8.28 (d, J=8.1 Hz,1H), 7.83 (t, J=7.1 Hz, 1H), 7.77-7.66 (m, 2H), 7.67-7.47 (m, 4H), 7.42(s, 1H), 7.31-7.21 (m, 3H), 7.08 (s, 1H), 4.11 (d, J=5.8 Hz, 2H),2.75-2.63 (m, 1H), 2.58 (m, 2H), 0.93 (t, J=7.2 Hz, 8H), 0.64 (m, 1H)),0.39-0.29 (m, 2H), −0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.79,−122.69; MS (ES+) 623.5 (M+1); 621.9 (M−1); Optical rotation:[α]_(D)=(−) 0.73 [0.055, CH₃OH]; Analysis calculated forC₃₃H₃₄F₄N₆02.3.5HCl.3.5H₂O: C, 48.73; H, 5.51; Cl, 15.26; N, 10.33;Found: C, 48.32; H, 5.79; Cl, 15.29; N, 10.73.

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244k) Step-1: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244f)

Compound 244f was prepared from (−)-tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244a) (175 mg, 0.27 mmol) and isovaleryl chloride (139 mg, 1.149 mmol)using the procedure as described for preparation of compound 244d inscheme-244 to furnish tert-butyl3-(5-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244f) (190 mg); MS (ES+) 737.6 (M+1), (ES−) 735.5 (M−1).

Step-2: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244k)

Free base of compound 244k was prepared from tert-butyl3-(5-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(244f) (190 mg) and HCl (4N in dioxane, 0.35 mL) using the procedure asdescribed for preparation of free base of compound 244i in scheme-244 toafford after purification by flash column chromatography (silica gel 12g, eluting with CHCl₃ in CMA-80 0-60%) (44 mg) free base of 244k as awhite solid. The free base was converted to hydrochloride salt asdescribed in preparation of hydrochloride salt of compound 244i from itsfree base in scheme-244 to afford(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(244k) (46 mg, 31% for 2 steps) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.72-8.62 (m, 2H), 8.51 (s, 1H),8.43 (bs, 3H), 8.25 (d, J=8.2 Hz, 1H), 7.87-7.77 (m, 1H), 7.73 (t, J=1.7Hz, 1H), 7.68 (s, 1H), 7.62 (m, 1H), 7.57-7.46 (m, 3H), 7.40-7.01 (m,3H), 4.11 (q, J=5.8 Hz, 2H), 2.60-2.54 (m, 2H), 2.17-2.05 (m, 2H), 1.88(m, 1H), 0.97 (m, 2H), 0.79 (m, 6H), 0.61 (m, 1H), 0.44-0.28 (m, 2H),−0.05-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80, −122.48; MS (ES+)637.6 (M+1); Optical rotation: [α]_(D)=(−) 2.61 [0.23, CH₃OH]; Analysiscalculated for C₃₄H₃₆FN₆O₂.2HCl.2.5H₂O: C, 54.11; H, 5.74; Cl, 9.40; N,11.14; Found: C, 53.98; H, 5.70; Cl, 9.78; N, 11.09.

Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(245c) Step-1: Preparation of tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245a)

To a solution of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(216c) (893 mg, 1.180 mmol) in MeOH (15 mL) cooled to 0° C. was addedHCl (0.89 mL, 3.56 mmol, 4 N in 1,4-dioxane) and stirred at about 0° C.for 2 h. The reaction mixture was quenched with triethylamine (0.610 mL,4.38 mmol) at 0° C. and concentrated in vacuum to dryness. The residuewas purified by flash column chromatography [silica gel, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1), then chloroform/CMA80 1:1) to give tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245a) (140 mg, 18.2%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.55 (s, 1H), 8.48-8.40 (m, 2H), 7.64-7.25 (m, 10H), 7.18 (t, J=9.4 Hz,1H), 4.19 (d, J=6.2 Hz, 2H), 2.21 (m, 2H), 1.38 (s, 9H), 1.15-0.90 (m,2H), 0.70-0.55 (m, 1H), 0.42-0.26 (m, 2H), −0.04 to −0.12 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −60.63, −123.81; MS (ES+): 653.5 (M+1).

Step-2: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245b)

To a solution of tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245a) (126 mg, 0.193 mmol) in pyridine (5 mL) was addedN,N-dimethylpyridin-4-amine (24.00 mg, 0.196 mmol), methanesulfonylchloride (0.018 mL, 0.232 mmol) and stirred at room temperature for 19h. Additional methanesulfonyl chloride (0.03 mL, 0.03 mL, 0.08 mL, 0.15mL, 0.15 mL) was added every day for five consecutive days and continuedheating at 70° C. overnight. The reaction mixture was diluted with ethylacetate (120 mL), washed with water (2×50 mL), brine (50 mL), dried overMgSO₄ filtered and concentrated in vacuum. The crude product waspurified by flash column chromatography [silica gel eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give tert-butyl3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245b) (30 mg, 21.3%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.54-8.50 (m, 2H), 7.85 (s, 1H), 7.65-7.17 (m, 11H), 4.18(d, J=6.2 Hz, 2H), 2.65-2.35 (m, 2H), 2.28 (s, 3H), 1.38 (s, 9H),1.15-0.90 (m, 1H), 0.93-0.71 (m, 1H), 0.64-0.48 (m, 1H), 0.39-0.20 (m,2H), −0.03-−0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80, −121.96;MS (ES+): 753.4 (M+23).

Step-3: Preparation of(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(245c)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(245b) (27 mg, 0.037 mmol) in ethanol (6 mL) was added conc. HCl (0.03mL, 0.366 mmol) and heated at reflux for 45 mins. The reaction mixturewas cooled to room temperature and concentrated to give1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(245c) (23 mg, 88%) hydrochloride salt as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.75 (s, 2H), 8.39 (s, 3H), 8.10 (s,1H), 7.77-7.45 (m, 8H), 7.33 (t, J=9.3 Hz, 1H), 7.29-7.20 (m, 1H), 4.12(d, J=5.6 Hz, 2H), 2.76-2.25 (m, 2H), 2.38 (s, 3H), 1.15-0.95 (m, 1H),0.90-0.70 (m, 1H), 0.65-0.50 (m, 1H), 0.40-0.25 (m, 2H), −0.01-−0.20 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.79, −121.16; MS (ES+): 631.4(M+1); Optical rotation: [α]_(D)=(−) 7.62 [0.105, CH₃OH]; Analysiscalculated for C₃₀H₃₀F₄N₆O₃S.2HCl.2H₂O: C, 48.72; H, 4.91; N, 11.36;Found: C, 48.61; H, 4.91; N, 10.99.

Preparation of(+)-1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylicacid (246f) Step-1: Preparation of methyl4-(furan-2-yl)-4-hydroxy-2-oxobut-3-enoate (246a)

To a solution of 1-(furan-2-yl)ethanone (229a) (13.76 g, 125 mmol) anddimethyl oxalate (14.76 g, 125 mmol) in THF (500 mL) was added dropwisesodium methoxide (25% in methanol, 29.7 g, 137 mmol). The resultingsuspension was stirred at room temperature for 18 h. The solid obtainedwas collected by filtration washed with ether to afford methyl4-(furan-2-yl)-4-hydroxy-2-oxobut-3-enoate (246a) (11.7 g, 59.6 mmol,47.7% yield) as a brown solid, which was taken as such for next step; ¹HNMR (300 MHz, DMSO-d₆) δ 8.33 (d, J=2.2 Hz, 1H), 7.81-7.73 (m, 2H), 7.56(dd, J=8.6, 2.2 Hz, 1H), 5.19 (d, J=13.2 Hz, 1H), 2.95 (s, 3H).

Step-2: Preparation of methyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (246b)

To methyl 4-(furan-2-yl)-4-hydroxy-2-oxobut-3-enoate (246a) (4 g, 20.39mmol) and 3-hydrazinylbenzonitrile hydrochloride (229c) (2.94 g, 17.33mmol) was added AcOH (40 mL) and stirred at room temperature overnight.The mixture was concentrated in vacuum and the residue obtained waspurified by flash column chromatography (silica gel 300 g, eluting 25%ethyl acetate in hexane) to furnish methyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (246b) as anyellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.10-8.01 (m, 2H), 7.89-7.82 (m,1H), 7.81-7.71 (m, 2H), 7.27 (s, 1H), 6.59 (dd, J=3.5, 1.8 Hz, 1H), 6.50(dd, J=3.5, 0.8 Hz, 1H), 3.87 (s, 3H); MS (ES+) 294.2 (M+1), 316.2(M+Na).

Step-3: Preparation of1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid(246c)

Compound 246c was prepared by oxidation of methyl1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (246b) (2 g,6.82 mmol) according to the procedure reported in step-5 of scheme-229to afford after purification by flash column chromatography (silica gel25 g, eluting with CMA80 in chloroform 0-100%)1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid(246c) (0.753 g, 41% yield) as an yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.02 (s, 1H), 7.94-7.77 (m, 2H), 7.72-7.59 (m, 1H), 7.01 (s,1H), 3.83 (s, 3H); MS (ES⁺): MS (ES+) 272.2 (M+1), 294.2 (M+Na), 565.3(2M+Na); MS (ES−) 270.2 (M−1), 541.3 (2M−1).

Step-4: Preparation of methyl1-(3-cyanophenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate(246d)

Compound 246d was prepared from1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid(246c) (0.706 g, 2.60 mmol) and (−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f) (0.844 g, 3.12 mmol) as described instep-3 of scheme-208 to afford methyl1-(3-cyanophenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate(246d) which was used as such without purification in the next step; MS(ES+) 524.4 (M+1); MS (ES−) 522.5 (M−1).

Step-5: Preparation methyl1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate(246e)

Compound 246e was prepared from methyl1-(3-cyanophenyl)-5-(5-((cyclopropylmethyllamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate(246d) (1.66 g, 3.17 mmol) according to the procedure reported forpreparation of compound 15g in step-6 of scheme-15 to furnish afterpurification by flash column chromatography (silica gel, eluting withCMA80 in chloroform from 0-100%) methyl1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate(246e) (0.126 g, 8% yield) as a white solid; MS (ES⁺): MS (ES+) 528.4(M+1); MS (ES−) 526.5 (M−1).

Step-6: Preparation of(+)-1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylicacid (246f)

To a solution of methyl1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246e) (0.119g, 0.226 mmol) in methanol (2.4 mL) and THF (2.4 mL) at room temperaturewas added aq. sodium hydroxide (2.256 mL, 2.256 mmol) and stirred atroom temperature for 2 h. Reaction mixture was quenched with acetic acid(0.155 mL, 2.71 mmol), stirred for 10 min and evaporated to dryness. Theresidue obtained was purified twice by flash column chromatography[silica gel 25 g, eluting with CMA80 in chloroform, 0-100%, secondcolumn: silica gel 12 g, eluting with methanol in chloroform from0-100%] to(+)-1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylicacid (246f) (19 mg, 16% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.37 (s, 1H, D₂O exchangeable), 8.13 (s, 1H), 7.58 (dd,J=7.4, 2.2 Hz, 1H), 7.44-7.09 (m, 12H), 4.81 (s, 1H), 4.15 (s, 2H), 2.26(d, J=6.7 Hz, 2H), 0.90 (dq, J=13.0, 6.9, 6.0 Hz, 1H), 0.42-0.28 (m,2H), 0.03 (dt, J=5.0, 2.7 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −123.25;MS (ES⁺): MS (ES+) 514.4 (M+1); MS (ES−) 512.4 (M−1); Optical rotation:[α]_(D)=(+) 2.86 [0.07, MeOH].

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247c) Step-1: Preparation ofN-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247a)

To a solution of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(89e) (200 mg, 0.440 mmol) in dichloromethane (12 mL) at 0° C. was addedsulfurous dichloride (0.070 mL, 0.946 mmol) and allowed to warm to roomtemperature over 2 h. The reaction mixture was concentrated in vacuum tofurnishN-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247a) which was used as such without further purification.

Step-2: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247b)

To a solution of pyridin-2-ol (216 mg, 2.200 mmol) in THF (5 mL) wasadded Lithium bis(dimethylsilyl)amide (2.20 mL, 2.200 mmol, 1 M in THF)stirred at room temperature for 0.5 h and concentrated in vacuum todryness. To this was added a solution ofN-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247a) in DMF (10 mL) and heated at 70° C. for 14 h. The reactionmixture was diluted with ethyl acetate (200 mL), washed with water (2×75mL), brine (75 mL), dried over MgSO₄ filtered and concentrated invacuum. The crude product was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 1:1)] to afford1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247b) (49 mg, 21%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.70 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.4 Hz, 1H),7.91 (m, 1H), 7.79-7.60 (m, 4H), 7.55 (t, J=1.8 Hz, 1H), 7.41-7.30 (m,2H), 7.17 (d, J=7.8 Hz, 1H), 6.44-6.38 (m, 1H), 6.23 (td, J=6.7, 1.5 Hz,1H), 6.13-6.05 (m, 1H), 2.30-2.14 (m, 2H), 1.29-0.92 (m, 2H), 0.80-0.61(m, 1H), 0.42-0.26 (m, 2H), 0.06-−0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.76; MS (ES+): 532.5 (M+1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247c)

Compound 247c was prepared from1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247b) (44 mg, 0.083 mmol) according to the procedure reported in step-6of scheme-89 for compound 89f to furnish after purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 9:1)]1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247c) (25 mg, 56.4%) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.75 (s, 1H), 7.67-7.54 (m, 4H), 7.52 (s, 1H), 7.47-7.27 (m,5H), 7.19-7.12 (m, 1H), 6.43-6.37 (m, 1H), 6.27-6.20 (m, 1H), 6.08 (t,J=8.1 Hz, 1H), 3.77 (s, 2H), 2.30-2.10 (m, 2H), 1.27-0.93 (m, 2H),0.77-0.60 (m, 1H), 0.37 (m, 2H), −0.05 to −0.10 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.51; MS (ES+) 536.5 (M+1).

Free base of compound 247c (18 mg, 0.034 mmol) was dissolved in methanol(1 mL), added 4 N HCl (aq. 0.034 mL) and concentrated in vacuum todryness. The residue was dissolved in water (0.5 mL) followed bylyopholization to obtain1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247c) hydrochloride as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.80(s, 1H), 8.31 (s, 3H), 7.71 (t, J=1.7 Hz, 1H), 7.66 (s, 2H), 7.65-7.51(m, 5H), 7.41-7.29 (m, 2H), 7.18 (d, J=7.8 Hz, 1H), 6.39 (dd, J=9.0, 1.4Hz, 1H), 6.23 (td, J=6.7, 1.5 Hz, 1H), 6.08 (t, J=8.0 Hz, 1H), 4.13 (q,J=5.8 Hz, 2H), 2.21 (m, 2H), 1.09 (m, 2H), 0.71 (m, 1H), 0.37 (m, 2H),−0.03 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.60; MS (ES+) 536.5(M+1), (ES−) 534.5 (M−1), 570.5 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247e) Step-1: Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247d)

Compound 247d was prepared fromN-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247a) (0.44 mmol) and pyrrolidin-2-one (0.169 mL, 2.200 mmol) accordingto the procedure reported for compound 247b in above step-2 of thisscheme to furnish after purification by flash column chromatography[silica gel with hexanes/ethyl acetate (1:0 to 1:1)]. Preparation of1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247d) (11 mg, 4.8%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 8.18 (t, J=1.9 Hz, 1H), 8.01 (dt, J=7.9, 1.3 Hz, 1H),7.95-7.89 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.65(d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.36-7.28 (m, 1H), 7.07 (d, J=7.6 Hz,1H), 5.09 (t, J=8.0 Hz, 1H), 2.39-2.16 (m, 2H), 2.07-1.70 (m, 6H),1.24-0.98 (m, 2H), 0.73 (m, 1H), 0.51-0.24 (m, 2H), 0.12-−0.15 (m, 2H);MS 522.4 (M+1), 544.5 (M+Na); (ES−) 520.4 (M−1).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247e)

Compound 247e was prepared from1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247d) (10 mg, 0.019 mmol) according to the procedure reported in step-6of scheme-89 for compound 89f to furnish after purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 9:1)]1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(247e) (3 mg) as an off white solid; ¹H NMR (300 MHz, MeOD) δ 7.55-7.35(m, 6H), 7.33-7.27 (m, 2H), 7.10 (m, 1H), 5.24-5.13 (m, 1H), 3.60 (s,2H), 3.45-3.30 (m, 1H), 3.05 (m, 1H), 2.49-2.32 (m, 2H), 2.09-1.84 (m,2H), 1.26-1.05 (m, 3H), 0.86 (m, 1H), 0.80-0.65 (m, 1H), 0.41 (m, 2H),0.06-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, MeOD) δ −64.55; MS (ES+) 526.4(M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248j) Step-1: Preparation of (E)-ethyl 3-cyclopropylacrylate (248b)

To a solution of 1-(triphenylphosphoranylidene)pentan-2-one (248a) (994g, 2853 mmol) in dichloromethane (3000 mL) was addedcyclopropanecarbaldehyde (200 g, 2853 mmol) and stirred at roomtemperature for 20 h. The reaction mixture was concentrated to ⅓ volumediluted with hexane (1000 mL) and concentrated in vacuum. The reactionmixture was diluted with hexane (3000 mL) stirred for 10 mins. The solidobtained of triphenylphospine oxide was removed by filtration. Thefiltrate was concentrated to afford (E)-ethyl 3-cyclopropylacrylate(248b) (410 g, 2925 mmol, 103% yield) as a colorless oil, which was usedas such for next step without purification; ¹H NMR (300 MHz, DMSO-d₆) δ6.38 (dd, J=15.4, 10.2 Hz, 1H), 5.93 (d, J=15.4 Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 1.64 (dtt, J=10.2, 8.0, 4.6 Hz, 1H), 1.19 (td, J=7.1, 1.0 Hz,3H), 0.98-0.82 (m, 2H), 0.75-0.62 (m, 2H).

Step-2: Preparation of ethyl 3-cyclopropylpropanoate (248c)

To a solution of (E)-ethyl 3-cyclopropylacrylate (248b) (290 g, 2069mmol) in methanol (2000 mL) cooled to 5° C. was added cobalt(II)chloride hexahydrate (24.61 g, 103 mmol) followed by dropwise additionof a solution of sodium tetrahydroborate (157 g, 4138 mmol) in DMF (500mL) at such a rate that internal temperature was not allowed to raiseabove 10° C. The reaction mixture was stirred for 1 h at 5° C., pouredinto water (5000 mL) and stirred for 15 mins. The resultant blacksuspended solution was filtered over celite pad, washed withdichloromethane (3×800 mL). The aqueous layer was separated andextracted with dichloromethane (2×600 mL). The dichloromethane layerswere combined, washed with water (2×1500 mL), brine, dried over MgSO₄,filtered and concentrated under vacuum with bath temperature below 40°C. to afford ethyl 3-cyclopropylpropanoate (248c) (260 g, 88% yield) ascolorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 4.03 (q, J=7.1 Hz, 2H),2.33 (t, J=7.3 Hz, 2H), 1.41 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H),0.75-0.59 (m, 1H), 0.40-0.31 (m, 2H), 0.06-−0.06 (m, 2H).

Step-3: Preparation of 3-cyclopropyl-N-methoxy-N-methylpropanamide(248d)

To a solution of ethyl 3-cyclopropylpropanoate (248c) (260 g, 1828 mmol)in THF (2000 mL) cooled to −10° C. was added N,O-dimethylhydroxylaminehydrochloride (268 g, 2743 mmol), followed by drop-wise addition ofisopropylmagnesiumchloride (2743 mL, 5485 mmol, 2 M in THF). The mixturewas stirred at −10° C. for 2 h, quenched with sat. NH₄Cl solution (4000mL) and allowed to warm to room temperature. The THF layer was separatedand aqueous layer was extracted with EtOAc (2×1000 mL). The organiclayers were combined washed with brine, dried over MgSO₄, filtered andconcentrated in vacuum to afford3-cyclopropyl-N-methoxy-N-methylpropanamide (248d) (240 g, 1527 mmol,83% yield) as an orange liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.66 (s,3H), 3.07 (s, 3H), 2.44 (t, J=7.6 Hz, 2H), 1.39 (q, J=7.3 Hz, 2H),0.76-0.62 (m, 1H), 0.42-0.31 (m, 2H), 0.08-−0.09 (m, 2H).

Step-4: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e)

To a solution of 3-cyclopropyl-N-methoxy-N-methylpropanamide (248d) (240g, 1527 mmol) in THF (2000 mL) cooled to 5° C. was added drop-wise afreshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(1908 mL, 1527 mmol, 1 M in THF) maintaining internal temperature around5° C. during addition. The reaction was stirred at 5° C. for 2 h,quenched with 3N HCl (1000 mL) and stirred for 2 h. The mixture wasbasified with solid NaHCO₃ and extracted with ethyl acetate (2×500 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuum to afford crude 248e. The crudematerial was dissolved in isopropanol (150 mL) and stirred over night.The solid obtained was collected by filtration washed with isopropanoland dried to afford 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one(248e) (90 g, 28.46% first crop) as a white solid. The filtrate wasconcentrated, kept at room temperature for 6 h and the solid obtainedwas collected by filtration to afford1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (50 g,15.81%, second crop) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.38(dd, J=8.9, 2.2 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 2.2 Hz, 1H), 7.09 (dd,J=11.1, 8.4 Hz, 1H), 5.41 (s, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.48 (q,J=7.2 Hz, 2H), 0.82-0.65 (m, 1H), 0.41-0.33 (m, 2H), 0.10-−0.02 (m, 2H);MS (ES+) 208.2 (M+1), (ES−) 206.2 (M−1); 19F NMR (282 MHz, DMSO-d₆) δ−128.24;

Step-5: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f)

To a solution of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one(248e) (13.63 g, 65.8 mmol) in THF (150 mL) and methanol (300 mL) at 0°C. was added sodium borohydride (5.08 g, 132 mmol) and stirred at 0° C.for 1 h. The reaction mixture was allowed to warm to room temperatureovernight. The reaction mixture was diluted with ethyl acetate (800 mL),neutralized with acetic acid, washed with water (2×300 mL), brine (300mL), dried over MgSO₄, filtered and concentrated in vacuum. The residuewas purified by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 4:1)] to afford1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f) (11.47 g,53.8 mmol, 83% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.86(dd, J=11.5, 8.2 Hz, 1H), 6.72 (dd, J=9.1, 2.1 Hz, 1H), 6.42 (ddd,J=8.3, 4.5, 2.1 Hz, 1H), 5.03 (s, 2H), 4.98 (d, J=4.1 Hz, 1H), 4.40-4.30(m, 1H), 1.71-1.48 (m, 2H), 1.26-1.01 (m, 2H), 0.73-0.54 (m, 1H),0.45-0.24 (m, 2H), 0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−138.16; MS (ES+) 210.1 (M+1); (ES−) 208.1 (M−1).

Step-6: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248g)

To a solution of1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)(2.419 g, 8.60 mmol) in DMF (40 mL) was added1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f) (1.5 g, 7.17mmol) N-ethyl-N-isopropylpropan-2-amine (7.50 mL, 43.1 mmol) andbromo-tris-pyrrolidino phosphoniumhexafluorophosphate(PyBrOP, 4.02 g,8.60 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 19 h under nitrogen atmosphere. The reaction was dilutedwith water (200 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were combined, washed with brine (50 mL), dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography [silica gel 40 g, elutingwith hexanes/ethyl acetate (1:0 to 4:1)] to furnish1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248g) (2.22 g, 66%) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 8.00(dt, J=7.7, 1.3 Hz, 1H), 7.94-7.88 (m, 1H), 7.79-7.68 (m, 2H), 7.49 (d,J=7.4 Hz, 1H), 7.27-7.16 (m, 2H), 5.22 (d, J=4.4 Hz, 1H), 4.52 (q, J=5.8Hz, 1H), 1.73-1.55 (m, 2H), 1.16 (m, 2H), 0.72-0.54 (m, 1H), 0.41-0.28(m, 2H), −0.02-−0.09 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.94, −124.07;MS (ES−) 471.5 (M−1).

Step-7:N-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248h)

To a solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248g) (645 mg, 1.365 mmol) in dichloromethane (36 mL) at 0° C. wasadded sulfurous dichloride (0.220 mL, 2.98 mmol) and allowed to warm toroom temperature over 2 h. The reaction mixture was concentrated invacuum to furnishN-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248h) which was used as such without further purification.

Step-8: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248i)

To a solution of pyridin-2-ol (669 mg, 6.83 mmol) in THF (15 mL) wasadded Lithium bis(dimethylsilyl)amide (6.90 mL, 6.90 mmol, 1 M in THF)stirred at room temperature for 0.5 h and concentrated in vacuum todryness. To this was added a solution ofN-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248h) (1.365 mmol) in DMF (10 mL) and heated at 70° C. for 14 h. Thereaction mixture was diluted with ethyl acetate (200 mL), washed withwater (2×75 mL), brine (75 mL), dried over MgSO₄ filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to1:1)] to furnish1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248i) (81 mg, 0.147 mmol, 10.8%) as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.13 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz,1H), 7.90 (d, J=8.4 Hz, 1H), 7.77-7.67 (m, 3H), 7.51 (d, J=7.1 Hz, 1H),7.41-7.23 (m, 3H), 6.42-6.37 (m, 1H), 6.24 (td, J=6.7, 1.5 Hz, 1H), 6.06(t, J=8.1 Hz, 1H), 2.22 (m, 2H), 1.32-0.92 (m, 2H), 0.75-0.60 (m, 1H),0.43-0.30 (m, 2H), −0.05 to −0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.95, −121.40; MS (ES+) 550.3 (M+1), 572.3 (M+Na), 548.3 (M−1).

Step-9: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248j)

Compound 248j was prepared from1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248i) (45 mg, 0.082 mmol) according to the procedure reported in step-6of scheme-89 for compound 89f to furnish after purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 9:1)]1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248j) (28 mg, 0.051 mmol, 61.8%) free base as a colorless gum; ¹H NMR(300 MHz, DMSO-d₆) δ 7.74-7.66 (m, 1H), 7.54 (d, J=18.6 Hz, 3H),7.45-7.38 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.27 (m, 2H), 6.43-6.35 (m,1H), 6.23 (td, J=6.7, 1.4 Hz, 1H), 6.05 (t, J=8.0 Hz, 1H), 3.77 (s, 2H),2.31-2.07 (m, 2H), 1.21-0.90 (m, 2H), 0.77-0.59 (m, 1H), 0.44-0.22 (m,2H), 0.10-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.72, −121.87.

The free base was dissolved in methanol (5 mL) added 4 N HCl (aq. 0.050mL) and concentrated in vacuum to afford1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248j) (29 mg, 89%) hydrochloride as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.44 (s, 3H), 7.80-7.26 (m, 10H), 6.43(d, J=9.1 Hz, 1H), 6.28 (t, J=6.7 Hz, 1H), 6.08 (t, J=8.0 Hz, 1H), 4.15(q, J=5.9 Hz, 2H), 2.25 (q, J=8.2, 6.8 Hz, 2H), 1.25-0.95 (m, 2H),0.80-0.65 (m, 1H), 0.45-0.35 (m, 2H), 0.13-−0.10 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.63, −121.38; MS (ES+): 554.4 (M+1).

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248k),(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248l)

Racemic1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248j)

(350 mg) was separated using Preparative SFC method. Column: 2.1×25 cmChiralPak AD-H from Chiral Technologies; CO₂ Co-solvent (Solvent B)Isopropanol with 1% Isopropylamine; Isocratic Method: 25% Co-solvent at80 g/min; System pressure 100 bar; Column temperature 40° C.; samplediluents methanol, to furnish:

-   -   1. Peak-1 corresponding to        (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (248l) (91.4 mg, >99.99% ee) as a white solid. ¹H NMR (300 MHz,        MeOD) δ 7.76 (d, J=7.4 Hz, 1H), 7.59 (dd, J=7.0, 1.9 Hz, 1H),        7.51 (s, 1H), 7.48-7.36 (m, 4H), 7.32 (s, 1H), 7.26 (m, 1H),        7.16 (t, J=9.5 Hz, 1H), 6.52 (ddd, J=9.1, 1.4, 0.7 Hz, 1H), 6.35        (td, J=6.8, 1.4 Hz, 1H), 6.19 (t, J=8.0 Hz, 1H), 3.84 (s, 2H),        2.35-2.13 (m, 2H), 1.36-0.97 (m, 2H), 0.79-0.62 (m, 1H),        0.49-0.31 (m, 2H), 0.01-−0.10 (m, 2H); ¹⁹F NMR (282 MHz, MeOD) δ        −64.56, −126.36; MS (ES+) 554.3 (M+1); (ES−) 552.3 (M−1);        Optical rotation: [α]_(D)=(−) 138.95 (MeOH, 0.535). Free base of        compound (248l) (87 mg, 0.157 mmol) was dissolved in methanol        (10 mL), filtered, added 4 N HCl (aq. 0.16 mL) and concentrated        in vacuum to dryness. The residue was dissolved in water (5 mL),        and lyophilized to afford HCl salt (59 mgs) as a white solid. H        NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.30 (s, 3H, D₂O        exchangeable), 7.77-7.65 (m, 3H), 7.64-7.48 (m, 4H), 7.35 (m,        3H), 6.39 (dd, J=9.2, 1.4 Hz, 1H), 6.24 (td, J=6.7, 1.5 Hz, 1H),        6.05 (t, J=8.1 Hz, 1H), 4.13 (d, J=5.8 Hz, 2H), 2.22 (m, 2H),        1.06 (m, 2H), 0.69 (m, 1H), 0.37 (m, 2H), −0.01-−0.07 (m, 2H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.83, −121.63; MS (ES⁺): MS (ES+)        554.3 (M+1); MS (ES−) 588.3 (M+Cl); Chiral Purity >99.99% ee;    -   2. Peak-2 corresponding to        (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide        (248k) (89.4 mgs, 98.2% ee); ¹H NMR (300 MHz, MeOD) δ 7.75 (s,        1H), 7.59 (d, J=6.9 Hz, 1H), 7.52 (s, 1H), 7.49-7.23 (m, 6H),        7.17 (t, J=9.5 Hz, 1H), 6.57-6.48 (m, 1H), 6.39-6.30 (m, 1H),        6.24-6.13 (m, 1H), 3.86 (s, 2H), 2.43-2.15 (m, 2H), 1.35-1.16        (m, 1H), 1.14-0.99 (m, 1H), 0.96-0.65 (m, 1H), 0.47-0.26 (m,        2H), −0.04-−0.09 (m, 2H); 19F NMR (282 MHz, MeOD) δ −64.57,        −126.35; Optical rotation: [α]_(D)=(+) 144.61 (MeOH, 0.52); Free        base of compound (248k) (82 mg, 0.148 mmol) was dissolved in        methanol (10 mL), filtered, added 4 N HCl (aq. 0.16 mL) and        concentrated in vacuum to dryness. The residue was dissolved in        water (5 mL), and lyophilized to afford HCl salt (65 mgs) as a        white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.36 (s,        3H), 7.75-7.66 (m, 3H), 7.64-7.48 (m, 4H), 7.41-7.25 (m, 3H),        6.39 (dd, J=9.1, 1.3 Hz, 1H), 6.24 (td, J=6.7, 1.4 Hz, 1H), 6.05        (t, J=8.1 Hz, 1H), 4.13 (t, J=5.5 Hz, 2H), 2.30-2.14 (m, 2H),        1.25-0.91 (m, 2H), 0.77-0.59 (m, 1H), 0.46-0.28 (m, 2H),        0.05-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.82, −121.62;        Chiral Purity 98.87% ee.

The following analytical method was used to check chiral purity ofcompounds 248k and 2431; Column: ChiraCel AD-H 250 mm/5 μm 4.6 mm;Solvent system: 80:20 Hexane/Ethanol with 0.1 TEA; Flow rate: 1.0 mL/mL;Column temperature: 25° C.; Injection volume: 5 μl; UV detection: 260nm.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249b) Step-1: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249a)

To a solution of pyrazin-2-ol (431 mg, 4.40 mmol) in THF (10 mL) wasadded LiHMDS (4.40 mL, 4.40 mmol, 1 M in THF), stirred at roomtemperature for 0.5 h and concentrated in vacuum to dryness. To this wasadded a solution ofN-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(248h) (0.88 mmol) in DMF (18 mL) and heated at 70° C. for 14 h. Thereaction mixture was diluted with ethyl acetate (200 mL), washed withwater (2×75 mL), brine (75 mL), dried over MgSO₄, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to1:1)] to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249a) (141 mg, 0.256 mmol, 29.1%) as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.02 (d, J=1.1Hz, 1H), 8.02-7.97 (m, 1H), 7.90 (dd, J=8.9, 1.8 Hz, 1H), 7.77 (dd,J=4.6, 1.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 7.40-7.27(m, 3H), 5.88 (t, J=8.0 Hz, 1H), 2.35-2.15 (m, 2H), 1.15-0.96 (m, 2H),0.75-0.60 (m, 1H), 0.44-0.25 (m, 2H), 0.05-−0.17 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.79, −120.66; MS (ES+) 551.4 (M+1); 573.4 (M+Na).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249b)

Compound 249b was prepared from1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249a) (124 mg, 0.225 mmol) according to the procedure reported instep-6 of scheme-89 for compound 89f to furnish after purification byflash column chromatography [silica gel, eluting withchloroform/methanol (1:0 to 9:1)] compound 248j (20 mg, 0.036 mmol,16.01%) free base as a brown solid. The free base was dissolved inmethanol (5 mL), added 4 N HCl (aq. 0.050 mL) and concentrated in vacuumto afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(249a) (21 mg, 92.19%) hydrochloride as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.72 (s, 1H), 8.41 (s, 3H), 8.02 (d, J=1.1 Hz, 1H),7.79 (dd, J=4.5, 1.2 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.68 (s, 1H),7.65-7.48 (m, 4H), 7.40-7.28 (m, 3H), 5.88 (dd, J=9.1, 7.0 Hz, 1H), 4.12(q, J=5.8 Hz, 2H), 2.37-2.13 (m, 2H), 1.21-0.96 (m, 2H), 0.78-0.60 (m,1H), 0.45-0.27 (m, 2H), 0.02-−0.07 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.84, −121.00; MS (ES+) 555.4 (M+1), (ES−) 553.4 (M−1).

Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b) Step-1: Preparation ofN-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250a)

To a solution of triphenylphosphine (0.833 g, 3.18 mmol) indichloromethane (30 mL) at 0° C. was added bromine (0.131 mL, 2.54 mmol)over a period of 2 mins. To the reaction at 0° C. was added dropwise apremixed solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.6 g, 1.270 mmol) and imidazole (0.216 g, 3.18 mmol) indichloromethane (30 mL). The reaction was stirred at 0° C. for 15 mins,allowed to warm to room temperature over a period of 1 h and dilutedwith dichloromethane (100 mL). The solution was passed through silicagel pad eluting with ethyl acetate in hexanes (20 to 30%) to affordN-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250a) (680 mg, 1.270 mmol, 100% yield) as a colorless semi solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.15 (t, J=1.9 Hz, 1H), 8.01(dt, J=7.7, 1.4 Hz, 1H), 7.92 (dt, J=8.5, 1.3 Hz, 1H), 7.79-7.71 (m,2H), 7.71-7.66 (m, 1H), 7.41 (m, 1H), 7.31 (m, 1H), 5.32 (t, J=7.5 Hz,1H), 2.39-2.09 (m, 2H), 1.37-1.20 (m, 2H), 0.70 (m, 1H), 0.38 (m, 2H),0.03-−0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97, −119.88,−122.84.

Step-2: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b)

To a solution of pyridin-2-ol (604 mg, 6.35 mmol) in acetonitrile (25mL) was added potassium carbonate (913 mg, 6.60 mmol) and heated toreflux for 1 h. The reaction was cooled to room temperature and added asolution ofN-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250a) (680 mg, 1.27 mmol) in acetonitrile (15 mL) and heated at 70° C.for 8 h. The reaction mixture was suspended in water (50 mL) andextracted with ethyl acetate (3×100 mL). The ethyl acetate layers werecombined washed with water (2×25 mL), brine (25 mL), dried, filtered andconcentrated in vacuum. The crude residue obtained was purified by flashcolumn chromatography [silica gel 12 g, eluting with a (9:1) mixture ofethyl acetate and methanol in hexanes (0 to 60%)] to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b) (151 mg, 0.275 mmol, 21.64% yield) as a syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.13 (s, 1H), 8.05 (ddd, J=5.0, 2.0, 0.8 Hz,1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.78-7.69 (m,2H), 7.69-7.64 (m, 1H), 7.57 (d, J=7.0 Hz, 1H), 7.38-7.18 (m, 2H), 6.91(ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.84 (dd, J=8.3, 1.0 Hz, 1H), 6.06 (dd,J=8.0, 5.3 Hz, 1H), 1.99 (s, 1H), 1.87 (s, 1H), 1.34-1.20 (m, 2H), 0.66(s, 1H), 0.36 (m, 2H), −0.01-−0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.94, −120.42-−124.83.

Step-3: Preparation of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b)

To a solution of1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b) (145 mg, 0.264 mmol) in methanol (5 mL) cooled with ice/water wasadded nickel(II) chloride hexahydrate (16.12 mg, 0.068 mmol), sodiumborohydride (64.4 mg, 1.669 mmol) in portions followed by stirring atroom temperature for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.064 mL, 0.609 mmol) and stirredat room temperature for 0.5 h. The reaction mixture was concentrated invacuum to remove methanol. The mixture was suspended in water (20 mL).The solid obtained was collected by filtration and purified by flashcolumn chromatography (silica gel 4 g, eluting with CMA 80 in chloroform0 to 100%) to afford1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(250b) (61 mg, 0.110 mmol, 41.8% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.14-8.00 (m, 1H), 7.72-7.64 (m,1H), 7.62 (d, J=7.1 Hz, 1H), 7.55 (d, J=17.3 Hz, 2H), 7.48-7.37 (m, 2H),7.33 (d, J=7.1 Hz, 1H), 7.30-7.16 (m, 2H), 6.91 (ddd, J=7.2, 5.0, 0.9Hz, 1H), 6.84 (dd, J=8.3, 0.9 Hz, 1H), 6.05 (dd, J=8.2, 5.4 Hz, 1H),3.78 (s, 2H), 1.98 (m, 1H), 1.86 (m, 1H), 1.25 (m, 2H), 0.79-0.56 (m,1H), 0.41-0.24 (m, 2H), −0.02-−0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −60.73, −123.02; MS (ES+) 554.3 (M+1), (ES−) 552.3 (M−1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(251e) Step-1: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251a)

To a solution of1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (4.42 g, 11.47 mmol) in DMF (25 mL) was added1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f) (2 g, 9.56mmol), N-ethyl-N-isopropylpropan-2-amine (8.32 mL, 47.8 mmol) andBromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (4.92 g,10.51 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 48 h under nitrogen atmosphere. The reaction wasdiluted with ethyl acetate (100 mL) washed with water (2×75 mL), brine(75 mL), dried, filtered, and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel 40 g,eluting with ethyl acetate in hexanes from 0-25%] to furnish tert-butyl3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251a) (4.04 g, 7.01 mmol, 73.3% yield) as a white foam; ¹H NMR (300MHz, DMSO-d₆) δ 10.56 (s, 1H), 7.60 (s, 1H), 7.51 (dd, J=14.3, 7.0 Hz,2H), 7.46-7.32 (m, 4H), 7.23-7.16 (m, 2H), 5.21 (d, J=4.4 Hz, 1H), 4.51(q, J=5.8 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.71-1.53 (m, 2H), 1.38 (s,9H), 1.34-1.07 (m, 2H), 0.74-0.56 (m, 1H), 0.43-0.24 (m, 2H), 0.03-−0.12(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.80, −124.41; MS (ES+) 599.3(M+Na); (ES−) 575.2 (M−1).

Step-2: Preparation of tert-butyl3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251b)

To a cold solution (ice-water bath) of tert-butyl3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251a) (2.04 g, 3.54 mmol) in THF (20 mL) was added PBr3 (0.112 mL,1.185 mmol). The resulting mixture was stirred for 40 min at 0° C. andquenched with water (50 mL). The reaction mixture was extracted withethyl acetate (2×25 mL). The organic layers were combined washed withwater and brine (50 mL), dried over anhydrous MgSO₄, filtered, andevaporated to dryness. The residue obtained was purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-25%] to furnish tert-butyl3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251b) (1.4 g, 2.189 mmol, 61.9% yield) as a White solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.64 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.61 (s, 1H),7.53-7.47 (m, 1H), 7.46-7.36 (m, 5H), 7.28 (d, J=9.0 Hz, 1H), 5.32 (t,J=7.5 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.37-2.07 (m, 2H), 1.37 (s, 9H),1.34-1.16 (m, 2H), 0.79-0.57 (m, 1H), 0.47-0.29 (m, 2H), 0.07-−0.10 (m,2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.82, −121.25; MS (ES+) 661.2, 663.2(M+Na).

Step-3: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251d)

To a solution of tert-butyl3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251b) (200 mg, 0.313 mmol) and N-methylhomopiperazine (251c) (143 mg,1.251 mmol) in N,N-dimethylformamide (2 mL) was added K₂CO₃ (173 mg,1.251 mmol). The reaction mixture was stirred at room temperature for 12h, quenched with water (10 mL) and extracted with EtOAc (3×50 mL). Theorganic layers were combined washed with water (50 mL), brine (25 mL),dried over MgSO₄, filtered and concentrated. The residue was purified byflash column chromatography (silica gel 24 g, eluting with 0-90% EtOAcin hexane then 0-40% CMA80 in CHCl₃) to furnish tert-butyl3-(5-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251d) (160 mg, 0.238 mmol, 76% yield) as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.56 (s, 1H), 7.60 (s, 1H), 7.54-7.29 (m, 6H), 7.26-7.10 (m,2H), 4.19 (d, J=6.3 Hz, 2H), 3.34 (s, 2H), 2.69-2.53 (m, 4H), 2.46-2.31(m, 2H), 2.19 (s, 3H), 1.98-1.80 (m, 1H), 1.71-1.53 (m, 2H), 1.38 (s,9H), 1.31-1.16 (m, 2H), 1.19-0.97 (m, 2H), 0.88-0.76 (m, 1H), 0.40-0.29(m, 2H), −0.01-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.80,−124.05.

Step 4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(251e)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251d) (156 mg, 0.232 mmol) in MeOH (3 mL) was added HCl (3N in MeOH,1.546 mL, 4.64 mmol), stirred at room temperature overnight andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 12 g, eluting with 0-80% CMA80 inCHCl₃), followed by reverse phase column chromatography (C₁₈ column 30g, eluting with 0-50% MeOH in H₂O) to furnish compound 251e (110 mg,0.192 mmol, 83% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.58 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.49-7.40 (m, 3H),7.41-7.32 (m, 2H), 7.27-7.09 (m, 2H), 3.82 (s, 2H), 3.59 (t, J=7.2 Hz,1H), 3.33-3.03 (m, 2H), 2.68-2.54 (m, 3H), 2.18 (s, 3H), 1.95-1.81 (m,1H), 1.76-1.47 (m, 4H), 1.33-0.92 (m, 5H), 0.70-0.57 (m, 1H), 0.41-0.22(m, 2H), −0.01-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75,−124.00.

To a solution of free base of compound 251e (89 mg, 0.155 mmol) in MeOH(10 mL) was added HCl (3N in MeOH, 0.389 mL, 1.554 mmol), stirred atroom temperature for 2 h and concentrated in vacuum. The residue wasdissolved in H₂O/ACN (10 mL, 9.5:0.5, v/v) and freeze-dried to give1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(251e) (72 mg, 0.126 mmol, 81% yield) hydrochloride as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.30-11.90 (m, 1H), 11.68-11.29 (m, 1H),11.07-10.81 (m, 1H), 8.58 (s, 3H), 7.88 (t, J=6.8 Hz, 1H), 7.82-7.70 (m,3H), 7.69-7.50 (m, 4H), 7.52-7.36 (m, 1H), 4.54 (s, 1H), 4.12 (d, J=5.3Hz, 2H), 3.97-3.48 (m, 4H), 3.47-3.20 (m, 3H), 2.82-2.62 (m, 3H),2.45-2.04 (m, 3H), 1.09-0.89 (m, 1H), 0.81-0.51 (m, 2H), 0.38-0.27 (m,2H), −0.04-−0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.81, −119.00;MS (ES⁺): MS (ES+) 573.3 (M+1).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-phenylprop-1-enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(252c) Step-1: Preparation of tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252a)

To a stirred solution of tert-butyl3-(5-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(211c) (1.603 g, 2.118 mmol) in methanol (18 mL) cooled to 0° C. wasadded 4 N hydrochloric acid in dioxane (1.6 mL, 6.40 mmol) and stirredat 0° C. for 2.5 h. The reaction mixture was quenched with triethylamine(1.100 mL, 7.89 mmol) and concentrated in vacuum to dryness. The residueobtained was purified by flash column chromatography [silica gel,eluting with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] tofurnish tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252a) (658 mg, 47.6%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.52 (s, 1H), 7.62-7.07 (m, 12H), 4.19 (d, J=6.2 Hz, 2H), 2.31-2.07 (m,4H), 1.38 (s, 9H), 1.11-0.90 (m, 2H), 0.91-0.74 (m, 1H), 0.71-0.53 (m,1H), 0.40-0.26 (m, 2H), −0.05-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −60.79, −123.62; MS (ES+) 652.4 (M+1), (ES−) 650.4 (M−1).

Step-2: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252b)

To a solution of tert-butyl3-(5-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252a) (145 mg, 0.222 mmol) in dichloromethane (10 mL) and pyridine(70.4 mg, 0.890 mmol) at 0° C. was added methanesulfonic anhydride (78mg, 0.445 mmol). The resulting reaction mixture was stirred at roomtemperature overnight. Additional DIPEA (0.078 mL, 0.445 mmol) andmethanesulfonic anhydride (78 mg, 0.445 mmol) was added and the mixturewas stirred at room temperature for 2 h. The reaction mixture wasdiluted with water (10 mL) extracted with dichloromethane (3×10 mL) Theorganic layers were combined dried over MgSO₄, filtered andconcentrated. The residue obtained was purified by flash columnchromatography (silica gel, 12 g eluting with EtOAc/hex, 0-50%) tofurnish tert-butyl 3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252b) (86 mg) as a white solid; MS (ES+) 752.4 (M+23), (ES−) 728.5(M−1).

Step-3: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-phenylprop-1-enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(252c)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(252b) (86 mg, 0.118 mmol) in methanol (20 mL) was added HCl (3Nanhydrous in MeOH, 2 mL) and heated at reflux for 30 min. The reactionwas concentrated in vacuum and the residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with CHCl₃ inCMA-80 0-60%) to furnish compound 252c (40 mg) free base as a whitesolid. The free base was dissolved in methanol (10 mL) and added HCl (3Nanhydrous in MeOH, 2 mL) at room temperature. The Solution wasconcentrated in vacuum to dryness and the residue was dissolved in water(2 mL) and two drops of acetonitrile, lyophilized to furnish1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-phenylprop-1-enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(252c) (42 mg, 0.079 mmol, 35.3% yield over 2 steps) hydrochloride saltas a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (2s, 1H), 8.38 (bs,3H), 7.75-7.64 (m, 2H), 7.66-7.56 (m, 1H), 7.56-7.21 (m, 7H), 7.20-7.09(m, 2H), 7.11-7.00 (m, 1H), 6.17 (dt, J=15.1, 7.5 Hz, 1H), 3.36 (s, 2H),1.94 (q, J=7.4 Hz, 2H), 0.87-0.68 (m, 1H), 0.49-0.29 (m, 2H), 0.14-−0.01(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.63, −60.64, −122.32, −122.64. (Eand Z mixture); MS (ES⁺): MS (ES+) 535.4 (M+1); 533.3.4 (M−1); Analysiscalculated for C₃₀H₂₆F₄N₄O.HCl.H₂O: C; 61.17, H; 4.96, N; 9.51; Found:C; 61.39, H; 5.02, N; 9.52.

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(253e) Step-1: Preparation of7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine(253a)

A solution of2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1(2H)-imine(235f) (2.88 g, 5.82 mmol) in TFA (10 mL) and anisole (5 mL) was heatedto 90° C. for 19 h, cooled to room temperature and concentrated invacuum. The residue was taken twice in MeOH (50 mL) and evaporated. ThepH of the residue was adjusted to 8.0 using saturated aqueous NaHCO₃,diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL).The combined organic layers were dried over anhydrous MgSO₄, filtered,evaporated to dryness. The residue obtained was purified by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate/methanol inhexanes from 0-100%] to furnish7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine(253a) (0.994 g, 49% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.47 (d, J=2.1 Hz, 1H), 7.97-7.83 (m, 2H), 7.79-7.72 (m, 1H),7.67 (dd, J=8.7, 2.0 Hz, 1H), 7.34 (s, 1H), 7.03 (d, J=5.8 Hz, 1H), 6.98(s, 2H, D₂O exchangeable), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 6.20 (dd,J=3.6, 0.8 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73; MS (ES−): MS(ES+) 345.2 (M+1); MS (ES−) 379.2 (M+Cl).

Step-2: Preparation of di-tert-butyl7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yliminodicarbonate(253b)

To a solution of7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine(253a) (12.177 g, 35.4 mmol) in acetonitrile (150 mL) was added DIPEA(14.83 mL, 85 mmol), (BOC)₂O (61.6 mL, 265 mmol) and DMAP (1.080 g, 8.84mmol). The mixture was heated at 50° C. overnight, cooled to roomtemperature and concentrated in vacuum. The residue was treated withbrine/water (100 mL/400 mL) and extracted with ethyl acetate (2×750 mL).The combined organics were dried over anhydrous MgSO₄, filtered,evaporated to dryness. The residue was purified by flash columnchromatography (silica gel 120 g, eluting with ethyl acetate in hexanesfrom 0-80%) to afford di-tert-butyl7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yliminodicarbonate(253b) (13.621 g, 71% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.56 (d, J=5.7 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.10-7.99 (m, 2H),7.91 (dd, J=8.8, 2.1 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.37 (s, 1H), 6.54(dd, J=3.5, 1.8 Hz, 1H), 6.39 (d, J=3.5 Hz, 1H), 1.27 (s, 18H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.99.

MS (ES⁺): MS (ES+): 567.2 (M+Na).

Step-3: Preparation of1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) and1-(1-(tert-butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (253f)

To a solution of di-tert-butyl7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yliminodicarbonate(253b) (5.70 g, 10.47 mmol) in t-BuOH (220 mL) was added 5% aq. sodiumdihydrogenphosphate (2.387 g, 19.90 mmol) in water (50 mL) followed bypotassium permanganate (3.31 g, 20.94 mmol). The reaction mixture wasstirred at room temperature for 13 h, quenched with 2-propanol (350 mL)and stirred at room temperature overnight. The reaction mixture wasfiltered through Celite washed with 2-propanol. The filtrate wasevaporated to dryness and purified by flash column chromatography(silica gel 80 g, eluting with CMA80 in chloroform from 0-100%) tofurnish compound 253c and 253f. Each compound were separately acidifiedwith 1N KHSO₄ (10 mL), extracted with ethyl acetate (2×30 mL), driedover anhydrous MgSO₄, filtered, concentrated in vacuum and dried overP205 to afford:

-   -   1.        1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic        acid (253c) (1.161 g, 2.222 mmol, 21% yield) as a yellow solid;        ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J=5.7 Hz, 1H), 8.21 (d,        J=8.7 Hz, 1H), 8.09-7.97 (m, 3H), 7.59 (s, 1H), 1.29 (s, 18H);        ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.97; MS (ES⁺): MS (ES+) 545.3        (M+Na); MS (ES−) 521.3 (M−1).    -   2.        1-(1-(tert-butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic        acid (253f) (0.481 g, 11% yield) as an yellow solid; ¹H NMR (300        MHz, DMSO-d₆) δ 8.36 (t, J=2.8 Hz, 1H), 8.29 (d, J=3.5 Hz, 1H),        8.10 (dd, J=8.8, 4.3 Hz, 1H), 7.99 (dd, J=8.5, 2.1 Hz, 1H),        7.76-7.66 (m, 1H), 7.60 (s, 1H), 1.46 (d, J=1.7 Hz, 9H); MS        (ES−) 421.2 (M−1), 843.2 (2M−1).

Step-4: Preparation di-tert-butyl7-(5-(5-(-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(253d)

Compound 253d was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (0.261 g, 0.500 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b) (0.234 g, 0.599 mmol) according to the procedure reported instep-3 of scheme-208 for compound 208c gave after workup crude 253d wasused as such in the next step; MS (ES⁺): MS (ES+) 916.6 (M+Na); MS (ES−)892.6 (M−1).

Step-5: Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(253e)

To a stirred solution of di-tert-butyl7-(5-(5-(-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(253d) (0.671 g, 0.751 mmol) in methanol (10 mL) was added 3M HCl (inMeOH, 3.75 mL) and heated at reflux for 1 h. The reaction mixture wascooled to room temperature and evaporated to dryness. The residue wasdissolved in water (25 mL) washed with MTBE (2×50 mL), the aqueous layerwas basified with 1N NaOH and extracted with ethyl acetate (2×50 mL).The ethyl acetate layers were combined dried over anhydrous MgSO₄,filtered, and evaporated to dryness. The residue obtained was purifiedby flash chromatography [silica gel 12 g (four separate columns),eluting with CMA80 in chloroform, 0-50%] to afford 253e (9 mg, 2% yield)free base as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.50 (s,1H, D₂O exchangeable), 8.50-8.34 (m, 3H), 7.88 (d, J=5.8 Hz, 1H), 7.78(d, J=8.8 Hz, 1H), 7.73-7.62 (m, 2H), 7.55 (dd, J=7.4, 2.4 Hz, 1H),7.39-7.32 (m, 2H), 7.28 (ddd, J=8.7, 4.8, 2.3 Hz, 1H), 7.16 (dd, J=10.1,8.7 Hz, 1H), 7.03-6.90 (m, 3H, D₂O exchangeable, 2H), 2.32 (s, 2H), 2.19(m, 2H), 1.02 (m, 2H), 0.61 (m, 1H), 0.39-0.19 (m, 2H), −0.11 (m, 2H);¹H NMR (300 MHz, DMSO-d₆, D₂O) δ 8.38 (td, J=5.6, 5.1, 1.8 Hz, 3H),7.90-7.75 (m, 2H), 7.71-7.59 (m, 2H), 7.49 (dd, J=7.2, 2.2 Hz, 1H),7.37-7.30 (m, 2H), 7.25 (ddd, J=9.0, 4.8, 2.4 Hz, 1H), 7.14 (t, J=9.4Hz, 1H), 7.00 (d, J=5.8 Hz, 1H), 2.26-2.07 (m, 2H), 0.97 (m, 2H), 0.57(m, 1H), 0.41-0.14 (m, 2H), −0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.71, −123.61; MS (ES+): MS (ES⁺): MS (ES+) 590.4 (M+1); (ES−) 588.4(M−1).

Compound 253e was treated with methanolic 3N HCl which afforded onevaporation and lyopholization(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(253e) hydrochloride salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.74 (s, 1H, D₂O exchangeable), 11.02 (s, 1H, D₂O exchangeable), 9.80(s, 3H, D₂O exchangeable), 9.42 (s, 3H, D₂O exchangeable), 8.95 (s, 1H),8.87 (m, 2H), 8.13 (d, J=1.8 Hz, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.72 (m,3H), 7.46 (d, J=7.8 Hz, 2H), 7.37 (d, J=7.0 Hz, 1H), 2.60 (m, 2H), 1.17(m, 2H), 0.69 (m, 1H), 0.34 (m, 2H), −0.00 (m, 2H); ¹H NMR (300 MHz,DMSO/D20-d₆) δ 8.91 (s, 1H), 8.87-8.80 (m, 2H), 8.15 (d, J=1.5 Hz, 2H),7.89 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.66 (m, 3H), 7.49 (t, J=9.4 Hz,1H), 7.41 (d, J=7.1 Hz, 1H), 7.35 (m, 1H), 2.56 (m, 2H), 1.14 (m, 2H),0.73 (m, 1H), 0.38 (m, 2H), 0.12-−0.09 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.89, −119.82; Analysis calculated forC₃₁H₂₇F₄N₇O.3HCl.3.5H₂O: C, 48.86; H, 4.89; Cl, 13.96; N, 12.87; Found;C, 48.62; H, 4.90; Cl, 14.37; N, 12.97; Optical rotation: [α]_(D)=(+)19.31 [0.29, MeOH].

Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(254c) Step-1: Preparation of1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicAcid (254a)

Compound 254a was prepared from7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine(253a) (0.275 g, 0.799 mmol) according to the procedure reported instep-2 of scheme-10 for preparation of compound 9i gave1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (254a) (0.077 g, 0.239 mmol, 29.9% yield) as a white solid; MS(ES+) 323.2 (M+1), 321.1 (M−1).

Step-2: Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(254b)

Compound 254b was prepared from1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (254a) [322 mg, 0.999 mmol, which was converted to HCl salt usingHCl (3N in MeOH, 3 mL) and concentrating in vacuum to dryness prior touse] and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(212e) (248 mg, 0.600 mmol) according to the procedure reported inscheme-237 for preparation of compound 237a gave after workup crude 254bwhich was used as such for next step.

Step-3: Preparation of(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(254c)

A solution of above crude containing1-(1-aminoisoquinolin-7-yl)-N-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(254b) in dioxane (5 mL) was added HCl (4N in dioxane, 2 mL) and heatedto reflux for 15 min. The solution was concentrated in vacuum and theresidue was taken in water washed with EtOAc (50 mL) to remove organicimpurities. The aqueous layer was basified with NaOH (1N) and extractedwith EtOAc (2×50 mL). The organic layer were combined, dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-40% CMA-80 inchloroform) to furnish(+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(254c) (17 mg, 0.028 mmol, 2.77% yield) free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.45-8.38 (m, 1H), 7.88 (d,J=5.8 Hz, 1H), 7.81-7.69 (m, 4H), 7.66 (dd, J=8.7, 2.0 Hz, 1H),7.59-7.48 (m, 3H), 7.30-7.13 (m, 2H), 7.03-6.93 (m, 3H), 2.31-2.17 (m,2H), 1.13-0.79 (m, 2H), 0.74-0.51 (m, 1H), 0.42-0.23 (m, 2H),−0.01-−0.24 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.74, −123.59; IR(KBr) 2230 cm⁻¹; Optical rotation: [α]_(D)=(+) 11.61 (0.155, methanol).

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(255a)

To a solution of1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (60 mg, 0.115 mmol) in DMF (5 mL) was added(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide(211b) (53.5 mg, 0.138 mmol), N-ethyl-N-isopropylpropan-2-amine (30.1 l,0.172 mmol) and bromo-tris-pyrrolidinophosphoniumhexafluorophosphate(PyBrop, 64.2 mg, 0.138 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 12h and diluted with ethyl acetate (100 mL) washed with water (2×50 mL).brine (50 mL), dried, filtered, and concentrated in vacuum to dryness tofurnish crude residue. The residue was dissolved in anhydrous dioxane (5mL), added HCl (4N in dioxane, 2 mL) and heated at 60° C. for 50 min.The reaction mixture was cooled to room temperature and concentrated invacuum to dryness. The residue was dissolved in water washed EtOAc (50mL). The aqueous layer was basified with NaOH (1N) and extracted withEtOAc (2×50 mL). The organic layer were combined, dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-40% CMA-80 inchloroform) to furnish compound 255a as a free base, which was convertedin to the HCl salt to furnish(+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(255a) (22 mg, 0.037 mmol, 32.5% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.22 (s, 4H), 8.86 (s,1H), 8.07 (s, 2H), 7.87 (s, 1H), 7.80 (d, J 20=7.0 Hz, 1H), 7.53 (dd,J=7.0, 2.0 Hz, 2H), 7.49-7.22 (m, 8H), 2.44 (d, J=8.3 Hz, 2H), 1.17-1.00(m, 2H), 0.72-0.53 (m, 1H), 0.38-0.23 (m, 2H), −0.03-−0.09 (m, 2H); ¹⁹FNMR (282 MHz, DMSO) δ −60.70, −120.69; MS (ES⁺): MS (ES+) 589.4 (M+1);587.4 (M−1); Optical rotation: [α]_(D)=(+) 8.42 (0.285, methanol);Analysis calculated for: C₃₂H₂₈F₄N₆O.2HCl.3H₂O; C, 53.71; H, 5.07; N,11.74; Found: C, 53.63; H, 4.98; N, 11.65.

Preparation of(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(256a)

To a solution of1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (40 mg, 0.077 mmol) in DMF (5 mL) was added(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (31.7 mg, 0.077 mmol), N-ethyl-N-isopropylpropan-2-amine (13.37l, 0.077 mmol) and bromo-tri s-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 35.7 mg, 0.077 mmol) at room temperature.The reaction mixture was stirred at room temperature for 12 h, dilutedwith ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL),dried, filtered, and concentrated in vacuum to dryness to furnish cruderesidue. The residue was dissolved in anhydrous dioxane (5 mL) added HCl(4N in dioxane, 2 mL) and heated at 60° C. for 50 min. The reactionmixture was cooled to room temperature and concentrated in vacuum todryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with 0-40% CMA-80 inchloroform) to furnish compound 256a as a free base, which was convertedin to the HCl salt to furnish(+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(256a) (7 mg, 0.011 mmol, 14.90% yield) hydrochloride as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 13.37 (s, 1H), 10.81 (s, 1H), 9.36 (s, 3H),9.16 (s, 3H), 8.83 (d, J=1.5 Hz, 1H), 8.07 (d, J=1.2 Hz, 2H), 7.92-7.81(m, 3H), 7.79 (d, J=6.9 Hz, 1H), 7.66-7.63 (m, 2H), 7.56-7.51 (m, 1H),7.42 (dd, J=10.0, 8.7 Hz, 1H), 7.31 (dd, J=7.4, 4.0 Hz, 2H), 2.61-2.38(m, 2H), 1.07 (m, 2H), 0.65 (m, 1H), 0.31 (m, 2H), −0.06 (m, 2H); ¹⁹FNMR (282 MHz, DMSO) δ −60.69, −120.30; MS (ES⁺): MS (ES+) 614.4 (M+1);612.4 (M−1); Optical rotation: [α]_(D)=(+) 15.38 (0.13, methanol).

Preparation of(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(257b) Step-1: Preparation of di-tert-butyl(7-(5-((5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yl)carbamate(257a)

Compound 257a was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (0.839 g, 1.60 mmol) and(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile(236f) (0.569 g, 1.927 mmol) according to the procedure reported instep-3 of scheme-208 for compound 208c gave after workup crude 257awhich was used as such in the next step; MS (ES+) 800.4 (M+1), 822.4(M+Na); MS (ES−) 798.4 (M−1).

Step-2: Preparation of(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(257b)

To a stirred solution of di-tert-butyl(7-(5-((5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yl)carbamate(257a)(2.58 g, 3.23 mmol) in dioxane (30 mL) was added 4M HCl (dioxane)(4.84 mL, 19.35 mmol) and heated at reflux for 1 h. The reaction wascooled to room temperature and evaporated to dryness. The residue wasdissolved in water (10 mL) washed with MTBE (2×50 mL), the aqueous layerwas basified with 1N NaOH and extracted with ethyl acetate (2×50 mL).The ethyl acetate layers were combined dried over anhydrous MgSO₄,filtered, and evaporated to dryness. The residue was purified by flashchromatography [first column; silica gel 24 g, eluting with ethylacetate/methanol (9:1) in hexanes 0-100%, second column; silica gel 12g, eluting with ethyl CMA80 in chloroform 0-100%, third column; silicagel 12 g, eluting with CMA80 in chloroform from 0-40%] to affordCompound 257b (0.10 g, 0.167 mmol, 5.17% yield) free base as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.52 (s, 1H, D₂O exchangeable), 8.42(d, J=2.0 Hz, 1H), 7.93-7.87 (m, 2H), 7.79 (d, J=8.7 Hz, 1H), 7.75-7.63(m, 4H), 7.59 (dd, J=7.5, 2.2 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.34 (m,1H), 7.21 (dd, J=10.3, 8.6 Hz, 1H), 6.98 (m, 3H, D₂O exchangeable, 2H),4.91 (s, 1H), 2.69 (bs, 1H), 2.24 (m, 2H), 0.88 (m, 1H), 0.52-0.23 (m,2H), 0.09-−0.06 (m, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 8.41 (d, J=2.0Hz, 1H), 7.92-7.80 (m, 3H), 7.69 (m, 4H), 7.62-7.56 (m, 1H), 7.51 (t,J=7.7 Hz, 1H), 7.35 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 7.21 (dd, J=10.2, 8.6Hz, 1H), 7.10-7.00 (m, 1H), 4.92 (s, 1H), 2.24 (m, 2H), 0.89 (m, 1H),0.49-0.27 (m, 2H), 0.05-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.73, −122.79; MS (ES⁺): MS (ES+) 600.3 (M+1); MS (ES−) 598.3 (M−1).

To a stirred solution of free base of 257b (0.093 g, 0.155 mmol) inmethanol (10 mL) was added HCl (3M in methanol) (0.517 mL, 1.551 mmol),stirred at room temperature for 1 h, evaporated to dryness, trituratedwith MTBE (50 mL), filtered, rinsed with MTBE, and dried. The residuewas dissolved in water, filtered, lyophilized to dryness afford(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(257b) (0.070 g, 0.117 mmol, 75% yield) hydrochloride salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H, D₂O exchangeable),10.24 (s, 2H, D₂O exchangeable), 9.09 (s, 2H, D₂O exchangeable), 8.83(s, 1H), 8.22 (s, 1H), 8.07 (s, 2H), 8.01 (d, J=7.9 Hz, 1H), 7.92 (dd,J=7.2, 2.3 Hz, 1H), 7.89-7.84 (m, 2H), 7.80 (d, J=6.9 Hz, 1H), 7.67 (q,J=7.4 Hz, 2H), 7.42 (dd, J=10.2, 8.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H),5.74 (s, 1H), 2.70 (m, 2H), 1.13 (d, J=11.9 Hz, 1H), 0.63-0.47 (m, 2H),0.29 (h, J=4.1 Hz, 2H); ¹H NMR (300 MHz, DMSO-d₆ D₂O) δ 8.81 (d, J=1.3Hz, 1H), 8.13 (t, J=1.7 Hz, 1H), 8.07 (d, J=1.4 Hz, 2H), 7.98-7.82 (m,4H), 7.78 (d, J=6.9 Hz, 1H), 7.72-7.57 (m, 2H), 7.50-7.39 (m, 1H), 7.31(d, J=6.9 Hz, 1H), 5.73 (s, 1H), 2.72 (m, 2H), 1.08 (m, 1H), 0.63-0.48(m, 2H), 0.28 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.88, −119.84; MS(ES+): MS (ES+) 600.3 (M+1); MS (ES−) 598.3 (M−1), 634.2 (M+Cl); Opticalrotation: (+) 0.73 [0.275, MeOH]; Analysis: calculated forC₃₂H₂₅F₄N₇O.2HCl.2H₂O: C, 54.24; H, 4.41; Cl, 10.01; N, 13.84; Found: C,54.37; H, 4.45; Cl, 9.79; N, 13.87.

Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(258g) Step-1: Preparation of methyl5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a)

To a solution of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one(248e) (0.207 g, 1.000 mmol) in dichloromethane (4 mL) at 0° C. wasadded pyridine (0.121 mL, 1.5 mmol) and methyl chloroformate (0.077 mL,1 mmol). The reaction was slowly warmed to room temperature overnightand evaporated to dryness. The residue was treated with water (25 mL)and extracted with ethyl acetate (2×50 mL), combined organics were driedover anhydrous MgSO₄, filtered, evaporated to dryness to afford methyl5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a) (0.254 g, 96%yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H, D₂Oexchangeable), 8.30 (dd, J=7.9, 2.2 Hz, 1H), 7.85-7.72 (m, 1H), 7.37(dd, J=10.6, 8.6 Hz, 1H), 3.69 (s, 3H), 3.06 (t, J=7.3 Hz, 2H), 1.51 (q,J=7.2 Hz, 2H), 0.85-0.65 (m, 1H), 0.47-0.33 (m, 2H), 0.12-0.02 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −117.74; MS (ES+): 266.1 (M+1); MS (ES−)264.2 (M−1).

Step-2: Preparation of methyl5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b)

Compound 258b was prepared from methyl5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a) (2.51 g, 9.46mmol) according to the procedure reported in step-5 of scheme-248 forpreparation of compound 248f gave after purification by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-50%] methyl5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b) (2.387g, 94% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s,1H, D₂O exchangeable), 7.70-7.51 (m, 1H), 7.18 (dd, J=10.6, 8.4 Hz, 1H),7.09 (ddd, J=8.4, 4.9, 2.1 Hz, 1H), 5.21 (d, J=4.4 Hz, 1H, D₂Oexchangeable), 4.60-4.43 (m, 1H), 3.69 (s, 3H), 1.68 (m, 2H), 1.21 (m,2H), 0.79-0.57 (m, 1H), 0.39 (m, 2H), 0.11-−0.09 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −127.49; MS (ES+): 290.2 (M+Na); MS (ES−) 266.2 (M−1).

Step-3: Preparation of methyl5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c)

Compound 258c was prepared from methyl5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b) (2.303g, 8.62 mmol) according to the procedure reported in step-2 ofscheme-251 for preparation of compound 251b gave after purification byflash column chromatography [silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%] methyl5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c) (1.289 g,3.90 mmol, 45.3% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ9.43 (s, 1H, D₂O exchangeable), 7.78 (dd, J=7.7, 2.0 Hz, 1H), 7.36-7.11(m, 2H), 5.29 (dd, J=8.1, 6.9 Hz, 1H), 3.67 (s, 3H), 2.41-2.06 (m, 2H),1.39-1.09 (m, 2H), 0.71 (m, 1H), 0.39 (m, 2H), 0.11-−0.09 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −124.45; MS (ES−) 328.1 (M−2).

Step-4: Preparation of methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(258d)

To a solution of methyl5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c) (1.21 g,3.66 mmol) in DMF (10 mL) was added pyridin-2(1H)-one (0.418 g, 4.40mmol) cesium carbonate (1.791 g, 5.50 mmol) and stirred at roomtemperature overnight. The reaction mixture was diluted with water (50mL), extracted with ethyl acetate (2×75 mL), combined organics weredried over anhydrous MgSO₄, filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [silica gel 24 g,eluting with ethyl acetate in hexanes from 0-50%] to furnish of methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(258d) (0.606 g, 48.0% yield) as a colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 9.37 (s, 1H, D₂O exchangeable), 7.76-7.58 (m, 2H), 7.36 (m,1H), 7.28-7.09 (m, 2H), 6.44-6.34 (m, 1H), 6.23 (td, J=6.7, 1.5 Hz, 1H),6.06 (t, J=8.0 Hz, 1H), 3.65 (s, 3H), 2.20 (m, 2H), 1.26-0.92 (m, 2H),0.80-0.63 (m, 1H), 0.46-0.30 (m, 2H), −0.01-−0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −125.28; MS (ES+) 367.3 (M+Na); MS (ES−) 343.3 (M−1).

Step-5: Preparation of1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(258e)

To a solution of methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(258d) (0.558 g, 1.620 mmol) in methanol (7 mL) was added 2.5 M NaOH(6.48 mL, 16.20 mmol) and refluxed for 13 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate (2×50 mL), combinedorganics were dried over anhydrous MgSO₄, filtered, evaporated todryness. The residue was purified by flash column chromatography [silicagel 12 g, eluting with ethyl acetate in hexanes from 0-25%] to furnishof 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(258e) (0.409 g, 88% yield) as an yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.59 (ddd, J=6.9, 2.1, 0.7 Hz, 1H), 7.35 (ddd, J=8.8, 6.5, 2.0 Hz,1H), 6.95 (dd, J=11.4, 8.3 Hz, 1H), 6.75 (dd, J=8.8, 2.2 Hz, 1H), 6.53(ddd, J=8.4, 4.3, 2.3 Hz, 1H), 6.44-6.33 (m, 1H), 6.21 (td, J=6.7, 1.5Hz, 1H), 5.99 (dd, J=9.0, 7.0 Hz, 1H), 5.20 (s, 2H), 2.14 (m, 2H),1.14-1.07 (m, 1H), 1.05-0.92 (m, 1H), 0.70 (m, 1H), 0.47-0.30 (m, 2H),0.00-−0.10 (m, 2H); MS (ES+): 309.2 (M+Na), MS (ES−) 285.2 (M−1), 321.2(M+Cl).

Step-6: Preparation of di-tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(258f)

Compound 258f was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (281 mg, 0.538 mmol) and1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(258e) (0.154 g, 0.538 mmol) according to the procedure reported instep-3 of scheme-208 for compound 208c gave after workup crudedi-tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(258f) as a brown wax which was used as such in next step; MS (ES+):813.5 (M+1).

Step-7: Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(258g)

To a stirred solution of di-tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(258f) (0.801 g, 1.013 mmol) in methanol (10 mL) was added HCl (3M inmethanol) (2.026 mL, 6.08 mmol) and heated at reflux for 1 h. Thereaction was cooled to room temperature and evaporated to dryness. Theresidue was basified with aq. ammonium hydroxide and evaporated todryness. The residue was purified by flash chromatography [silica gel 12g, eluting with CMA80 in chloroform from 0-100%]. The sample wasdissolved in minimum amount of methanol/1N HCl, and purified by “reversephase” flash chromatography [C₁₈ column, eluting with water (0.1% TFA)in methanol from 0-100%]. The compound isolated was triturated withmethanolic 3N HCl, and sonicated and evaporated to dryness. The residuewas dissolved in minimum amount of acetonitrile and water, lyophilizedto afford1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(258g) (10 mg, 2% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 13.38 (s, 1H, D₂O exchangeable), 10.71 (s, 1H, D₂Oexchangeable), 9.20 (s, 3H, D₂O exchangeable), 8.84 (s, 1H), 8.09 (s,2H), 7.85-7.75 (m, 2H), 7.70 (dd, J=7.0, 2.0 Hz, 1H), 7.54 (s, 1H), 7.34(dd, J=8.9, 4.8 Hz, 3H), 6.39 (d, J=9.0 Hz, 1H), 6.23 (t, J=6.6 Hz, 1H),6.04 (t, J=8.0 Hz, 1H), 2.20 (m, 2H), 1.05 (m, 2H), 0.76-0.62 (m, 1H),0.42-0.31 (m, 2H), −0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.70,−121.04; MS (ES+): 591.3 (M+1); MS (ES−) 625.3 (M+Cl); Analysiscalculated for C₃₁H₂₆F₄N₆O₂.2HCl.2H₂O: C, 53.23; H, 4.61; N, 12.01;Found: C, 53.18; H, 4.56; N, 12.38.

Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(259d) Step-1: Preparation of methyl5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(259a)

To a solution of methyl5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c) (0.925 g,2.80 mmol) in DMF (10 mL) was added pyrazin-2(1H)-one (0.323 g, 3.36mmol) cesium carbonate (0.867 g, 2.66 mmol) and stirred at roomtemperature overnight. The reaction mixture was diluted with water (50mL), extracted with ethyl acetate (2×75 mL), combined organics weredried over anhydrous MgSO₄, filtered and evaporated to dryness. Theresidue was purified by flash column chromatography [silica gel 24 g,eluting with ethyl acetate/methanol (9:1) in hexanes from 0-75%] tofurnish methyl5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(259a) (0.304 g, 31% yield) as a colorless wax. MS (ES+): 368.3 (M+Na),MS (ES−) 344.2 (M−1).

Step-2: Preparation of1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrazin-2(1H)-one(259b)

Compound 259b was prepared from methyl5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(259a) (301 mg, 0.872 mmol) according to the procedure reported instep-5 of scheme-258 for compound 258e to afford after purification byflash column chromatography [silica gel 12 g, eluting with ethylacetate/methanol (9:1) in hexanes from 0-75%)1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrazin-2(1H)-one(259b) (61 mg, 24% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.02 (d, J=1.2 Hz, 1H), 7.65 (d, J=4.6 Hz, 1H), 7.33 (d, J=4.5 Hz, 1H),6.97 (dd, J=11.4, 8.3 Hz, 1H), 6.76 (dd, J=8.8, 2.3 Hz, 1H), 6.57 (dt,J=7.3, 3.4 Hz, 1H), 5.81 (t, J=8.0 Hz, 1H), 5.22 (s, 2H, D₂Oexchangeable), 2.18 (m, 2H), 1.08 (m, 2H), 0.69 (m, 1H), 0.43-0.29 (m,2H), −0.02 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −135.69; MS (ES+):310.2 (M+Na), MS (ES−) 286.3 (M−1), 322.2 (M+Cl).

Step-3: Preparation of tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(259c)

Compound 259c was prepared from and1-(1-(tert-butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253f) (0.102 g, 0.242 mmol) and1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrazin-2(1H)-one(259b) (58 mg) according to the procedure reported in step-3 ofscheme-208 for compound 208c gave after workup crude tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(259c) (359 mg) as a brown wax which was used as such in next step; MS(ES+) 692.2 (M+1).

Step-4: Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(259d)

To a solution of crude tert-butyl7-(5-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(259c) (0.338 g, crude reaction mixture) in methanol (10 mL) was added 3M methanolic HCl (0.977 mL, 2.93 mmol) and heated at reflux for 1.5 h.The reaction was cooled to room temperature and evaporated to dryness.The residue was basified with aq. ammonium hydroxide and evaporated todryness. The residue was purified by flash chromatography [silica gel 12g, eluting with CMA80 in chloroform from 0-100%] to afford compound 259d(12 mg, 4% yield) free base as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H, D₂O exchangeable), 8.57-8.38(m, 1H), 8.07 (d, J=1.1 Hz, 1H), 7.94 (d, J=5.7 Hz, 1H), 7.88-7.69 (m,4H), 7.66-7.58 (m, 1H), 7.44-7.30 (m, 3H), 7.10-6.94 (m, 3H), 5.92 (dd,J=9.0, 6.9 Hz, 1H), 2.41-2.17 (m, 2H), 1.12 (m, 2H), 0.73 (m, 1H),0.49-0.31 (m, 2H), 0.04-−0.04 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.73, −120.86; MS (ES+) 592.3 (M+1), 614.2 (M+Na); MS (ES−) 590.3(M−1), 626.3 (M+Cl).

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(260b) Step-1: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(260a)

Compound 260a was prepared from tert-butyl3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(251b) (0.7 g, 1.09 mmol) and pyrrolidine-2,5-dione (0.217 g, 2.19 mmol)according to the procedure reported in step-4 of scheme-258 forpreparation of compound 258d gave after purification by flash columnchromatography (silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-50%) to tert-butyl3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(260a) (0.19 g, 0.29 mmol, 26.4% yield) as colorless foam; ¹H NMR (300MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.59 (m, 2H), 7.53-7.14 (m, 7H), 5.07(dd, J=9.5, 6.4 Hz, 1H), 4.20 (d, J=6.2 Hz, 2H), 2.70-2.57 (m, 4H),2.47-2.31 (m, 1H), 2.16 (m, 1H), 1.37 (s, 11H), 0.66 (s, 1H), 0.37 (m,2H), −0.01-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −60.85, −121.00; MS(ES+) 680.3 (M+Na).

Step-2: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(260b)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(260a) (0.15 g, 0.23 mmol) in methanol (5 mL) was added hydrogenchloride in 3 M in methanol (0.76 mL, 2.28 mmol) and stirred at roomtemperature for 20 h. The solution was concentrated in vacuum andresultant residue was partitioned between NaHCO₃ solution (40 mL) andEtOAc (30 mL). Layers were separated; aqueous layer was extracted withEtOAc (25 mL). The combined organics were washed with brine, dried overMgSO₄, filtered and concentrated in vacuum. The residue was purified byflash chromatography (silica gel 12 g, eluting with 0-100% CMA80 inchloroform) to afford1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(260b) (0.105 g, 0.188 mmol, 83% yield) as colorless foam; ¹H NMR (300MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.32 (s, 1H), 7.71-7.14 (m, 9H), 5.07(dd, J=9.5, 6.4 Hz, 1H), 3.80 (s, 2H), 2.70-2.57 (m, 4H), 2.43 (m, 1H)2.16 (m, 1H), 1.10 (m, 2H), 0.64 (m, 1H), 0.37 (m, 2H), −0.00 (m, 2H).¹⁹F NMR (282 MHz, DMSO) δ −60.75, −122.08; MS (ES+) 558.3 (M+1).

Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(261k) Step-1: Preparation ofN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(261a)

Compound 261a was prepared from1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (19.5 g, 94mmol) and 2-methylpropane-2-sulfinamide (14.83 g, 122 mmol) according tothe procedure reported in step-1 of scheme 208 for preparation ofcompound 208a (reaction time 62 h) to afford after purification by flashcolumn chromatography [silica gel with hexanes/ethyl acetate (1:0 to4:1, then 2:1, 1:1)] to giveN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(261a) (14.26 g, 48.9%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.33 (d, J=8.9 Hz, 1H), 7.10-7.03 (m, 2H), 5.39 (s, 2H), 3.32-3.04 (m,2H), 1.54-1.36 (m, 2H), 1.21 (s, 9H), 0.82-0.66 (m, 1H), 0.53-0.27 (m,2H), 0.15-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −129.99; MS (ES+):333.2 (M+Na).

Step-2: Preparation ofN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(261b)

Compound 261b was prepared fromN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(261a) (4 g, 12.89 mmol) according to the procedure reported in step-5of scheme 248 for preparation of compound 248f (reaction temp −78° C.)to affordN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(261b) (4.15 g) as a light yellow gum which was used as such for nextstep.

Step-3: Preparation of methyl5-(3-cyclopropyl-1-(1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(261c)

To a biphasic solution ofN-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(261b) (4.5 g, 14.40 mmol) in ethyl acetate (100 mL) and saturatedaqueous NaHCO₃ (100 mL) was added methyl chloroformate (1.673 mL, 21.60mmol) and stirred at room temperature for 16 h. Aqueous layers wasseparated, extracted with ethyl acetate (2×150 mL) and combined organiclayers were washed with brine, dried over MgSO₄, filtered, concentratedand purified by flash column chromatography to afford methyl5-(3-cyclopropyl-1-(1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(261c) (4.86 g, 13.12 mmol, 91% yield) as gummy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.30 (s, 1H), 7.69-7.52 (m, 1H), 7.25-6.98 (m, 2H), 5.60 (d,J=8.2 Hz, 1H), 4.12 (m, 1H), 3.66 (s, 3H), 1.97-1.79 (m, 1H), 1.68 (m,1H), 1.08 (m, 11H), 0.63 (m, 1H), 0.42-0.26 (m, 2H), −0.01-−0.12 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.03 (d, J=44.3 Hz).

Step-4: Preparation of methyl5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (261d)

To a stirred solution of methyl5-(3-cyclopropyl-1-(1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(261c) (4.85 g, 13.09 mmol) in methanol (100 mL) was added hydrochloricacid 4N solution in 1,4-dioxane (16.36 mL, 65.5 mmol) and stirred atroom temperature for 30 minutes. The reaction was concentrated invacuum, residue was dissolved in water (100 mL) basified with saturatedsodium bicarbonate solution and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with water (2×50 mL), brine (50mL), dried, filtered and concentrated in vacuum to afford methyl5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (261d) (3.57 g,13.41 mmol, 102% yield) as a thick syrup which was used as such for nextstep; ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 7.75-7.39 (m, 1H),7.30-6.85 (m, 2H), 3.65 (s, 3H), 3.37 (m, 1H), 2.04 (s, 2H), 1.59 (m,2H), 1.27-1.13 (m, 1H), 1.08-0.91 (m, 1H), 0.73-0.51 (m, 1H), 0.41-0.24(m, 2H), −0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.68.

Step-5: Preparation of methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261e)

To a stirred solution of methyl5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (261d) (3.2 g,12.02 mmol) in dichloromethane (70 mL) was addeddihydro-2H-pyran-2,6(3H)-dione (1.508 g, 13.22 mmol). The reaction wasstirred at room temperature for 30 mins added acetyl chloride (17.09 mL,240 mmol) and heated at reflux for 2 h. The reaction was concentrated invacuum and purified by flash column chromatography (silica gel, 40 g,eluting with ethyl acetate in hexanes 0 to 100%) to afford methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261e) (4.078 g, 11.25 mmol, 94% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.25-6.90 (m,2H), 5.71 (dd, J=9.2, 6.5 Hz, 1H), 3.65 (s, 3H), 2.62 (m, 4H), 2.37-2.12(m, 2H), 1.88-1.75 (m, 2H), 1.20-0.99 (m, 2H), 0.68 (m, 1H), 0.47-0.32(m, 2H), 0.05-0.00 (m, 1H), −0.01-−0.07 (m, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −127.01.

Step-6: Preparation of methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261f)

To a stirred solution of methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261e) (3.55 g, 9.80 mmol) in dichloromethane (200 mL) at −78° C. wasadded diisobutylaluminum hydride (29.4 mL, 29.4 mmol) and stirred at−78° C. for 1 h. Reaction was quenched with methanol (3 mL) and warmedto room temperature. Reaction was diluted with 2 N sodium hydroxide (4mL) washed with saturated disodium tartarate solution. The layers wereseparated and aqueous layer was extracted with dichloromethane (2×150mL). the organic layers were combined washed with brine (100 mL), dried,filtered and concentrated to afford methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261f) (3.204 g, 8.79 mmol, 90% yield) which was used as such for nextstep; ¹H NMR (300 MHz, DMSO-d₆) δ 9.51-9.07 (m, 1H), 7.68-7.41 (m, 1H),7.37-6.95 (m, 2H), 5.58 (dd, J=30.4, 6.5 Hz, 1H), 5.45 (m, 0.5H), 4.96(m, 0.5H), 4.87 (m, 0.5H), 4.62 (m, 0.5H), 3.65 (2s, 3H), 2.35-1.99 (m,4H), 1.81-1.59 (m, 2H), 1.59-1.36 (m, 2H), 1.27-1.06 (m, 2H), 0.70 (m,1H), 0.45-0.25 (m, 2H), 0.05-−0.18 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−126.93.

Step-7: Preparation of methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(261g)

To a stirred solution of methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(261f) (3.2 g, 8.78 mmol) in dichloromethane (100 mL) cooled to 0° C.was added triethylamine (7.34 mL, 52.7 mmol) and methanesulfonylchloride (1.369 mL, 17.56 mmol). The reaction was allowed to warm toroom temperature and stirred for 30 min. The reaction was diluted withdichloromethane (200 mL) and water (50 mL). The aqueous layer wasseparated and extracted with dichloromethane (2×50 mL). The organiclayers were combined washed with water (2×25 mL), brine (25 mL), driedand concentrated. The crude residue was purified by flash columnchromatography (silica gel, 40 g eluting with ethyl acetate in hexanes 0to 50 to 100%) to afford methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(261g) (2.35 g, 6.78 mmol, 77% yield) as a clear syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 9.35 (s, 1H), 7.58 (dd, J=8.0, 2.1 Hz, 1H), 7.18 (dd, J=10.6,8.5 Hz, 1H), 7.06 (m, 1H), 6.15 (dt, J=7.9, 1.6 Hz, 1H), 5.64 (dd,J=9.9, 6.2 Hz, 1H), 5.17 (dt, J=8.4, 4.4 Hz, 1H), 3.66 (s, 3H), 2.43 (m,2H), 2.20 (m, 2H), 2.08-1.80 (m, 2H), 1.25-1.00 (m, 2H), 0.71 (m, 1H),0.45-0.31 (m, 2H), 0.05 (m, 1H), 0.00-−0.08 (m, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −126.28.

Step-8: Preparation of1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(261h)

Compound 261h was prepared from methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(261g) (1.2 g, 3.46 mmol) according to the procedure reported in step-5of scheme 248 for preparation of compound 258e to afford1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(261h) (0.89 g, 3.09 mmol, 89% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 6.91 (dd, J=11.5, 8.4 Hz, 1H), 6.69 (dd,J=8.8, 2.3 Hz, 1H), 6.44 (m, 1H), 6.09 (dt, J=7.8, 1.6 Hz, 1H), 5.56(dd, J=10.1, 5.9 Hz, 1H), 5.20-5.06 (m, 3H), 2.48-2.35 (m, 2H),2.27-2.12 (m, 2H), 1.98-1.77 (m, 2H), 1.16-0.93 (m, 2H), 0.78-0.63 (m,1H), 0.44-0.33 (m, 2H), 0.10-−0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−137.03.

Step-9: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261i)

Compound 261i was prepared from1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.53 g, 1.38 mmol) and1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(261h) (0.4 g, 1.39 mmol) according to the procedure reported in step-3of scheme 208 for preparation of compound 208c to afford afterpurification by flash column chromatography (silica gel 40 g, elutingwith ethyl acetate in hexanes from 0-40%) tert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261i) (0.48 g, 0.73 mmol, 52.8% yield) as colorless foam; ¹H NMR (300MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.60 (s, 1H), 7.44 (ddd, J=26.7, 13.8,5.9 Hz, 6H), 7.31-7.15 (m, 2H), 6.17 (d, J=7.9 Hz, 1H), 5.71-5.57 (m,1H), 5.25-5.08 (m, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.49-2.35 (m, 2H),2.27-2.12 (m, 2H), 2.05-1.88 (m, 2H), 1.37 (s, 9H), 1.27 (m, 1H),1.16-1.01 (m, 1H), 0.71 (m, 1H), 0.38 (m, 2H), −0.00 (m, 2H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ −122.72, −60.80.

Step-10: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261j)

Palladium(II)hydroxide (6.43 mg, 0.023 mmol) was added to a solution oftert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261i) (0.15 g, 0.23 mmol) in ethyl acetate (5 mL) and mixture washydrogenated under H₂ atmosphere for 36 h. Mixture was filtered overcelite pad, washed with EtOAc (2×10 mL), concentrated in vacuum andpurified by flash column chromatography (silica gel 24 g, eluting withethyl acetate in hexanes from 0-40%) to afford tert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261j) (0.09 g, 0.137 mmol, 59.8% yield) as gummy mass; ¹H NMR (300 MHz,DMSO-d₆) δ 10.60 (s, 1H), 7.60 (s, 1H), 7.42 (m, 6H), 7.23 (dt, J=13.4,6.7 Hz, 2H), 5.77 (t, J=8.0 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 3.16-3.00(m, 1H), 2.82-2.64 (m, 1H), 2.39-2.18 (m, 2H), 1.99 (m, 3H), 1.74-1.43(m, 3H), 1.37 (s, 9H), 1.30 (m, 1H), 1.08 (m, 1H), 0.72 (m, 1H), 0.38(m, 2H), −0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −123.10, −60.81.

Step-11: Preparation of(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(261k)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(261j) (0.09 g, 0.137 mmol) in methanol (4 mL) was added HCl (0.46 mL,1.37 mmol, 3 M in methanol), stirred at room temperature for 20 h andconcentrated in vacuum. The residue was partitioned between NaHCO₃solution (40 mL) and EtOAc (30 mL). Layers were separated, aqueous layerwas extracted with EtOAc (25 mL) and combined organics were washed withbrine, dried over MgSO₄, filtered concentrated. The residue was purifiedby flash column chromatography [silica gel 12 g, eluting with CMA80 andchloroform from 0-30%] to afford(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(261k) (0.06 g, 0.11 mmol, 79% yield) as colorless foam; ¹H NMR (300MHz, DMSO-d₆) δ 10.59 (s, 1H), 7.58 (s, 1H), 7.54-7.38 (m, 4H),7.38-7.10 (m, 3H), 5.76 (t, J=8.0 Hz, 1H), 3.78 (s, 2H), 3.16-3.00 (m,1H), 2.72 (dd, J=12.2, 6.2 Hz, 1H), 2.29 (q, J=6.8 Hz, 2H), 1.95 (dd,J=15.5, 8.1 Hz, 2H), 1.76-1.43 (m, 4H), 1.34-0.96 (m, 3H), 0.91-0.65 (m,2H), 0.38 (m, 2H), 0.11-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.14, −60.74; MS(ES+) 558.3 (M+1); MS(ES−) 556.3 (M−1), 592.3 (M+Cl).Optical rotation: [α]_(D)=(+) 49.12 [0.285, MeOH].

Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(262f) Step-1: Preparation of5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262a)

Compound 262a was prepared from(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b) (0.5 g, 1.284 mmol) according to the procedure reported in step-1of scheme 258 for preparation of compound 258a to afford5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262a) (0.573 g, 100% yield) as a yellow solid which was used as such innext step; ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.53-8.45 (m, 2H),7.67 (d, J=7.5 Hz, 1H), 7.34-7.28 (m, 2H), 7.21-7.08 (m, 2H), 5.51 (s,1H), 3.64 (s, 3H), 2.71-2.40 (m, 2H), 1.15 (s, 9H), 1.10-0.85 (m, 2H),0.73-0.55 (m, 1H), 0.43-0.29 (m, 2H), −0.02-−0.11 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −126.83; MS (ES⁺): MS (ES+) 448.3 (M+1); MS (ES−) 446.3(M−1), 482.3 (M+Cl).

Step-2: Preparation of methyl5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262b)

To a stirred solution of5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262a) (0.551 g, 1.231 mmol) in methanol (12 mL) was added 3M methanolicHCl (2.462 mL, 7.39 mmol) and heated at reflux. The reaction was cooledto room temperature, concentrated in vacuum, basified with saturatedaqueous NaHCO₃ solution and extracted with ethyl acetate (2×30 mL). Thecombined organic layer was dried over anhydrous MgSO₄, filtered,evaporated to dryness to afford methyl5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262b) (0.418 g, 1.217 mmol, 99% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.53-8.35 (m, 2H), 7.64 (d, J=7.6 Hz, 1H),7.42-7.31 (m, 2H), 7.25-7.04 (m, 2H), 3.63 (s, 3H), 2.35 (s, 2H), 2.20(t, J=8.1 Hz, 2H), 1.12-0.91 (m, 2H), 0.73-0.56 (m, 1H), 0.41-0.29 (m,2H), −0.03-−0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.63; MS(ES⁺): MS (ES+) 344.2 (M+1); MS (ES−) 342.2 (M−1).

Step-3: Preparation of methyl5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262c)

To a stirred solution of methyl5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262b) (0.401 g, 1.168 mmol) in dichloromethane (20 mL) at 0° C. wasadded pyridine (0.471 mL, 5.84 mmol), methanesulfonic anhydride (0.407g, 2.336 mmol). The resulting mixture was allowed to warm to roomtemperature overnight. Additional pyridine (0.471 mL, 5.84 mmol) andmethanesulfonic anhydride (0.407 g, 2.336 mmol) was added and mixturewas stirred for another 3 h at room temperature. Reaction mixture wasdiluted with brine (20 mL), extracted with dichloromethane (2×30 mL),combined organic layers were dried over anhydrous MgSO₄, filtered,evaporated to dryness. The residue was purified by flash columnchromatography [silica gel 12 g, eluting with CMA80 in chloroform from0-75%] to afford methyl5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate(262c) (0.489 g, 1.160 mmol, 99% yield) which was used as such in nextstep; MS (ES⁺): MS (ES+) 444.2 (M+Na); MS (ES−) 456.2 (M+Cl).

Step-4: Preparation of(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)methanesulfonamide(262d)

Compound 262d was prepared from methyl 5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate (262c)(0.483 g, 1.146 mmol) according to the procedure reported in step-5 ofscheme 258 for preparation of compound 258e to afford(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)methanesulfonamide(262d) (0.311 g, 0.856 mmol, 74.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.61-8.30 (m, 2H), 7.67 (s, 1H), 7.37-7.18 (m, 2H), 6.95(dd, J=11.2, 8.5 Hz, 1H), 6.82 (dd, J=8.9, 2.4 Hz, 1H), 6.50-6.36 (m,1H), 5.21 (s, 2H), 2.66-2.54 (m, 1H), 2.35-2.24 (m, 1H), 2.21 (s, 3H),1.15-0.97 (m, 1H), 0.87-0.67 (m, 1H), 0.64-0.47 (m, 1H), 0.40-0.20 (m,2H), −0.02-−0.20 (m, 2H); MS (ES+): MS (ES−) 362.2 (M−1), 725.3 (2M−1);Optical rotation: [α]_(D)=(+) 21.0 [0.2, MeOH].

Step-5: Preparation of di-tert-butyl 7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(262e)

Compound 262e was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c)(0.519 g, 0.994 mmol) and(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)methanesulfonamide(262d) (0.301 g, 0.828 mmol) according to the procedure reported instep-3 of scheme 208 for preparation of compound 208c to afforddi-tert-butyl7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(262e), the crude reaction mixture was used as such in the next step; MS(ES+): 868.3 (M+1).

Step-6: Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(262f)

Compound 262f was prepared from di-tert-butyl7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(262e) (1.439 g, 1.658 mmol) according to the procedure reported instep-7 of scheme 258 for preparation of compound 258f to afford afterpurification compound 262f (78 mg, 7% yield) yellow solid as afree-base; ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.69-8.45 (m, 2H),8.43 (s, 1H), 7.98-7.51 (m, 6H), 7.40-7.14 (m, 3H), 7.10-6.84 (m, 3H),2.31-2.22 (m, 2H), 2.27 (s, 3H), 1.21-0.93 (m, 2H), 0.90-0.71 (m, 1H),0.65-0.48 (m, 1H), 0.38-0.20 (m, 2H), −0.05-−0.21 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −60.70, −121.52;

To a solution of free base of compound 262f (0.069 g, 0.103 mmol) inmethanol (10 mL) was added HCl (3M in methanol) (0.207 mL, 0.620 mmol),evaporated to dryness, dissolved in minimum amount of water andlyophilized to afford(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(262f) (34 mg, 49% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 13.67 (s, 1H, D₂O exchangeable), 10.90 (s, 1H, D₂Oexchangeable), 9.33 (s, 2H, D₂O exchangeable), 8.99-8.85 (m, 1H), 8.78(d, J=6.0 Hz, 2H), 8.19-8.03 (m, 3H), 7.89 (s, 1H), 7.90-7.67 (m, 3H),7.67-7.55 (m, 1H), 7.39-7.21 (m, 3H), 2.76-2.41 (m, 2H), 2.39 (s, 3H),1.11-0.95 (m, 1H), 0.88-0.69 (m, 1H), 0.65-0.50 (m, 1H), 0.38-0.19 (m,2H), −0.02-−0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.90, −120.70;¹H NMR (300 MHz, DMSO-d₆/D₂O) δ 8.97 (s, 1H), 8.91-8.83 (m, 2H),8.30-8.14 (m, 2H), 8.00-7.84 (m, 4H), 7.76 (dd, J=7.2, 2.4 Hz, 1H),7.54-6.79 (m, 3H), 2.86-2.58 (m, 2H), 2.55 (s, 3H), 1.26-1.04 (m, 2H),1.05-0.83 (m, 1H), 0.80-0.62 (m, 1H), 0.53-0.32 (m, 2H), 0.11-−0.08 (m,2H); MS (ES⁺): MS (ES+) 668.2 (M+1), 702.2 (M+Cl); Optical rotation:[α]_(D)=(−) 2.0 [0.1, MeOH]; Analysis calculated for:C₃₂H₂₉F₄N₇₀₃S52.25HCl.4.25H₂O: C, 46.51; H, 4.85; Cl, 9.65; N, 11.87;Found: C, 46.66; H, 4.56; Cl, 9.27; N, 12.03.

Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(263d) Step-1: Preparation of methyl(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)carbamate(263a)

To a suspension of uracil (1 g, 8.92 mmol) in acetonitrile (60 mL) wasadded N,O-bis trimethylsilyl acetamide (BSA, 4.54 g, 22.30 mmol) andstirred for 30 min. To the reaction mixture was added methyl5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (528c) (3.54 g,10.71 mmol), iodine (0.226 g, 0.892 mmol) and heated at reflux until allstarting material was consumed. The reaction mixture was cooled to roomtemperature, concentrated in vacuum, diluted with ethyl acetate (100mL), and washed with H₂O (50 mL). The organic layer was dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel 40 g, eluting with 0-90% EtOAc inhexane) to furnish methyl5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(263a) (785 mg, 0.498 mmol, 24.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.33 (s, 1H), 9.40 (s, 1H), 7.72 (d, J=8.0 Hz, 1H),7.65 (d, J=6.2 Hz, 1H), 7.29-7.16 (m, 1H), 7.19-7.09 (m, 1H), 5.58 (t,J=7.5 Hz, 2H), 3.66 (s, 3H), 2.24-2.05 (m, 2H), 1.24-1.02 (m, 2H),0.75-0.64 (m, 1H), 0.46-0.32 (m, 2H), 0.05-−0.03 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −125.34; MS (ES+) 362.2 (M+1), 360.2 (M−1).

Step-2: Preparation of1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrimidine-2,4(1H,3H)-dione(263b)

Compound 263b was prepared from methyl5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(263a) (765 mg, 2.117 mmol) according to the procedure reported instep-5 of scheme 258 for preparation of compound 258e to afford afterpurification by flash column chromatography [silica gel 12 g, elutingwith 0-60% ethyl acetate in hexanes]1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrimidine-2,4(1H,3H)-dione(263b) (450 mg, 1.484 mmol, 70.1% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 11.31 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 6.96(dd, J=11.2, 8.5 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.56-6.48 (m, 1H),5.57 (d, J=6.3 Hz, 1H), 5.49 (t, J=7.7 Hz, 1H), 5.21 (s, 2H), 2.21-1.97(m, 2H), 1.21-1.00 (m, 2H), 0.76-0.59 (m, 1H), 0.42-0.32 (m, 2H),0.10-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −136.17.

Step-3: Preparation of tert-butyl3-(5-((5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(263c)

Compound 263c was prepared from1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrimidine-2,4(1H,3H)-dione(263b) (410 mg, 1.352 mmol) and1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (781 mg, 2.027 mmol) according to the procedure reported instep-3 of scheme 208 for preparation of compound 208c to afford afterpurification by flash column chromatography [silica gel 24 g, elutingwith 0-90% EtOAc/MeOH (9:1, v/v) in hexane] tert-butyl3-(5-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(263c) (325 mg, 0.485 mmol, 35.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.35 (s, 1H), 10.64 (s, 1H), 7.74 (d, J=8.0 Hz, 1H),7.64-7.25 (m, 9H), 5.59 (d, J=8.0 Hz, 2H), 4.20 (d, J=6.1 Hz, 2H),2.30-2.04 (m, 2H), 1.37 (s, 9H), 1.24-1.00 (m, 2H), 0.77-0.61 (m, 1H),0.43-0.31 (m, 2H), 0.08-−0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.82, −121.69; MS (ES⁺), 693.2 (M+Na); (ES−) 669.3 (M−1).

Step-4: Preparation of1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(263d)

To a solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(263c) (300 mg, 0.447 mmol) in MeOH (15 mL) was added HCl (3N in MeOH)(1.193 mL, 3.58 mmol) and heated at reflux for 40 min. The solution wascooled to room temperature concentrated in vacuum and the residue waspurified by flash column chromatography (silica gel 12 g, eluting with0-60% CMA80 in CHCl₃) to furnish1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(263d) (140 mg, 0.245 mmol, 54.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.74 (d, J=8.0 Hz, 1H), 7.63-7.48 (m, 3H), 7.48-7.39 (m,2H), 7.38-7.25 (m, 3H), 5.60 (m, 2H), 3.78 (s, 2H), 2.26-2.05 (m, 2H),1.22-0.98 (m, 2H), 0.77-0.62 (m, 1H), 0.45-0.32 (m, 2H), 0.00 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.75, −121.72; MS (ES+), 571.3 (M+1),569.3 (M−1).

Preparation of(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(264g) Step-1: Preparation of(R)-2-methyl-N-(pyridin-4-ylmethylene)propane-2-sulfinamide (264a)

Compound 264a was prepared from isonicotinaldehyde (11.67 g, 109 mmol)and (R)-2,4,6-triisopropylbenzenesulfinamide (12 g, 99 mmol) accordingto the procedure reported in step-1 of scheme-222 for the preparation ofcompound 222a to afford after purification by flash columnchromatography (silica gel 120 g, eluting with ethyl acetate in hexanesfrom 0-70%) (R)-2-methyl-N-(pyridin-4-ylmethylene)propane-2-sulfinamide(264a) (15.60 g, 75% yield) as a crystalline pale yellow solid; ¹H NMR:¹H NMR (300 MHz, DMSO-d₆) δ 8.84-8.77 (m, 2H), 8.63 (s, 1H), 7.94-7.81(m, 2H), 1.21 (s, 9H); MS (ES⁺): MS (ES+): 211.2 (M+1); Opticalrotation: [α]_(D)=(−) 99.25 [0.935, MeOH].

Step-2: Preparation of(R)—N—((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide(264b) and(R)—N—((R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide(264c)

Compounds 264b and 264c was prepared from(R)-2-methyl-N-(pyridin-4-ylmethylene)propane-2-sulfinamide (264a)(10.73 g, 51 mmol) and freshly prepared3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (107mL, 81 mmol) according to the procedure reported in step-2 of scheme-222for the preparation of compound 222b and 222c to afford afterpurification by flash column chromatography [silica gel 120 g, elutingwith CMA80 in chloroform, 0-100%] to afford;

-   -   1.        (R)—N—((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide        (264b) (6.979 g, 43% yield) as a light red solid; ¹H NMR (300        MHz, DMSO-d₆) δ 8.58-8.42 (m, 2H), 7.43-7.26 (m, 2H), 6.93 (dd,        J=11.5, 8.3 Hz, 1H), 6.80-6.66 (m, 1H), 6.64-6.50 (m, 1H), 6.02        (d, J=6.1 Hz, 1H), 5.40 (d, J=6.1 Hz, 1H), 5.15 (s, 2H, D₂O        exchangeable), 1.14 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ        −136.78; MS (ES⁺): MS (ES+) 322.2 (M+1), 344.2 (M+Na); MS (ES−)        320.3 (M−1); Optical rotation: [α]_(D)=(−) 27.41 [0.54, MeOH].    -   2.        (R)—N—((R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide        (264c) (5.26 g, 32% yield) as a yellow solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 8.59-8.44 (m, 2H), 7.48-7.31 (m, 2H), 6.92 (dd,        J=11.4, 8.3 Hz, 1H), 6.69 (dd, J=8.9, 2.2 Hz, 1H), 6.58-6.41 (m,        1H), 6.10 (d, J=6.3 Hz, 1H), 5.36 (d, J=6.2 Hz, 1H), 5.14 (s,        2H, D₂O exchangeable), 1.14 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆)        δ −136.73; MS (ES⁺): MS (ES+) 322.2 (M+1), 344.2 (M+Na); MS        (ES−) 320.3 (M−1), 356.2 (M+Cl); Optical rotation: [α]_(D)=(−)        77.2 [0.5, MeOH].

Step-3: Preparation of (+)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline(264d)

Compound 264d was prepared from(R)—N—((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide(264b) (2.26 g, 7.03 mmol) according to the procedure reported in step-3of scheme-222 for the preparation of compound 222d to afford afterpurification by flash column chromatography [silica gel 40 g, elutingwith methanol in chloroform, 0-100%](+)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (264d) (0.344 g, 22%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55-8.38 (m, 2H),7.44-7.23 (m, 2H), 6.88 (dd, J=11.5, 8.3 Hz, 1H), 6.74 (dd, J=8.9, 2.2Hz, 1H), 6.62-6.48 (m, 1H), 5.06 (s, 2H, D₂O exchangeable), 4.92 (s,1H), 2.26 (s, 2H, D₂O exchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−137.67; MS (ES⁺): MS (ES+) 218.2 (M+1); MS (ES−) 216.1 (M−1); Opticalrotation: [α]_(D)=(+) 47.55 [0.235, MeOH].

Step-4: Preparation of(+)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(264e)

Compound 264e was prepared from(+)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (264d) (0.331 g, 1.524mmol) according to the procedure reported in step-4 of scheme-222 forthe preparation of compound 222f to afford after purification by flashcolumn chromatography (silica gel 12 g, eluting with 0-50% CMA80 inchloroform in hexanes)(+)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(264e) (0.326 g, 1.201 mmol, 79% yield) as a yellow oil; ¹H NMR (300MHz, DMSO-d₆) δ 8.53-8.41 (m, 2H), 7.48-7.32 (m, 2H), 6.96-6.73 (m, 2H),6.63-6.45 (m, 1H), 5.10 (s, 2H, D₂O exchangeable), 4.69 (s, 1H),2.50-2.39 (m, 1H), 2.34-2.17 (m, 2H), 0.98-0.83 (m, 1H), 0.48-0.31 (m,2H), 0.10-−0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.28; MS (ES⁺):MS (ES+) 272.2 (M+1), MS (ES−) 270.2 (M−1); Optical rotation:[α]_(D)=(+) 41.65 [0.485, MeOH].

Step-5: Preparation of bis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(264f)

Compound 264f was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (0.595 g, 1.139 mmol) and(+)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(264e) (0.309 g, 1.139 mmol) according to the procedure reported instep-3 of scheme 208 for preparation of compound 208c to affordbis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(264f) as a brown waxy solid which was used as such in next step.

Step-6:(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(264g)

Compound 264g was prepared from bis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(264f) (1.4202 g, 1.831 mmol) according to the procedure reported instep-7 of scheme 258 for preparation of compound 258f to afford afterpurification compound 264g as a free-base. The free base was convertedto hydrochloride salt to afford after lypholization(+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(264g) (64 mg, 6% yield) hydrochloride salt as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 13.74 (s, 1H, D₂O exchangeable), 10.96 (s,1H, D₂O exchangeable), 10.76 (s, 1H, D₂O exchangeable), 9.55-9.18 (m,2H, D₂O exchangeable), 8.99-8.74 (m, 3H), 8.29-8.13 (m, 2H), 8.10 (s,1H), 8.00 (d, J=6.6 Hz, 1H), 7.93 (s, 1H), 7.88-7.66 (m, 2H), 7.42 (t,J=9.4 Hz, 1H), 7.39-7.22 (m, 1H), 5.93 (s, 1H), 2.73 (s, 2H), 1.36-1.06(m, 1H), 0.53 (m, 2H), 0.43-0.10 (m, 2H); ¹H NMR (300 MHz, DMSO/D20-d₆)δ 8.92-8.74 (m, 3H), 8.10 (s, 2H), 7.94 (d, J=5.6 Hz, 2H), 7.94-7.84 (m,1H), 7.81 (s, 1H), 7.75 (d, J=6.9 Hz, 1H), 7.66-7.55 (m, 1H), 7.44 (t,J=9.4 Hz, 1H), 7.36 (d, J=7.1 Hz, 1H), 5.85 (s, 1H), 2.98-2.68 (m, 2H),1.19-1.00 (m, 1H), 0.71-0.52 (m, 2H), 0.31 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.86, −118.92; MS (ES⁺): MS (ES+) 576.2 (M+1), 610.2(M+Cl); HPLC: HPLC (Reverse phase, UV Absorbance 260 nm; Rt=3.010 min(98.17%)]; Optical rotation: [α]_(D)=(+) 23.40 [0.265, MeOH]; Analysiscalculated for: C₃₀H₂₅F₄N₇O.3HCl.4H₂O: C, 47.60; H, 4.79; Cl, 14.05; N,12.95; Found: C, 47.41; H, 4.80; Cl, 13.88; N, 12.87.

Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(265d) Step-1: Preparation of(−)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (265a)

Compound 265a was prepared from(R)—N—((R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide(264c) (2.61 g, 8.12 mmol) according to the procedure reported in step-3of scheme-222 for the preparation of compound 222d to afford afterpurification by flash column chromatography [silica gel 40 g, elutingwith methanol in chloroform, 0-100%](−)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (265a) (1.736 g, 98%yield) as a reddish yellow oil which was used as such in the next step;MS (ES⁺): MS (ES+) 218.2 (M+1); MS (ES−) 216.1 (M−1); Optical rotation:[α]_(D)=(−) 62.35 [0.51, MeOH].

Step-2: Preparation of(−)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(265b)

Compound 265b was prepared from(−)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (265a) (1.79 g, 8.24mmol) according to the procedure reported in step-4 of scheme-222 forthe preparation of compound 222f to afford after purification by flashcolumn chromatography (silica gel 40 g, eluting with 0-100% CMA80 inchloroform)(−)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(265b) (0.089 g, 4% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.68-8.35 (m, 2H), 7.52-7.28 (m, 2H), 6.99-6.74 (m, 2H), 6.64-6.44 (m,1H), 5.09 (s, 2H), 4.68 (s, 1H), 2.51-2.36 (m, 1H), 2.37-2.18 (m, 2H),1.00-0.81 (m, 1H), 0.48-0.32 (m, 2H), 0.11-0.00 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −137.26; MS (ES⁺): MS (ES+) 272.3 (M+1); MS (ES−) 270.3(M−1).

Step-3: Preparation of bis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(265c)

Compound 265c was prepared from1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (81 mg, 0.155 mmol) and(−)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline(265b) (50 mg, 0.186 mmol) according to the procedure reported in step-3of scheme 208 for preparation of compound 208c to afford crudebis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(265c) which was used as such in next step.

Step-4: Preparation of(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(265d)

To a solution of crude bis-di-tert-butyl7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate(265c) from above step in anhydrous dioxane (5 mL) was added HCl (4N indioxane, 2 mL) and heated at 60° C. for 50 min. The reaction mixture wascooled to room temperature and concentrated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography (silica gel40 g, eluting with 0-40% CMA-80 in chloroform) to furnish compound 265das a free base, which was converted to the HCl salt to afford(−)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(265d) (25 mg, 0.043 mmol, 28.0% yield) hydrochloride as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.87 (s, 1H), 10.48 (s, 2H),9.26 (s, 2H), 8.76-8.69 (m, 2H), 8.09 (m, 2H), 8.01-7.84 (m, 5H), 7.80(d, J=7.0 Hz, 1H), 7.77-7.71 (m, 1H), 7.42 (dd, J=10.3, 8.6 Hz, 1H),7.33 (d, J=7.0 Hz, 1H), 5.80 (d, J=7.2 Hz, 1H), 2.83-2.62 (m, 2H),1.26-1.05 (m, 1H), 0.65-0.44 (m, 2H), 0.42-0.21 (m, 2H); MS (ES+) 576.4(M+1); 574.4 (M−1); Optical rotation: [α]_(D)=(−) 16 [0.25, MeOH];Analysis calculated for C₃₀H₂₅F₄N₇O.3HCl.3.5H₂O: C, 48.17; H, 4.72; N,13.11; Found: C, 48.29; H, 4.70; N, 12.88.

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (266j) Step-1: Preparation of 2-methyl-isonicotinic Acid (266b)

To a solution of 2, 4-dimethyl-pyridine (266a) (100 g, 933.245 mmol) inwater (1000 mL) was added potassium permanganate (294.97 g, 1866.489mmol) portion-wise over a period of 2 h. The resulting reaction mixturewas heated at 80° C. for 12 h. The reaction mixture was cooled to roomtemperature, filtered through celite bed and filtrate was concentratedunder reduced pressure to a volume of 250 mL at 50° C. The obtainedsolution was cooled to 0° C. and pH was adjusted to 3 using 1N HCl(temperature between 0° C. to 5° C.). The solid obtained was collectedby filtration washed with chilled water and dried to afford2-methylisonicotinic acid (266b) (22.3 g, yield: 17.42%); ¹H NMR (D₂O) δ8.52 (s, 1H), 7.94-7.90 (m, 2H), 2.69 (s, 3H); MS (+) 138.1 (M+1).

Step-2: Preparation of N-methoxy-N,2-dimethylisonicotinamide (266c)

To a stirred solution of 2-methylisonicotinic acid (266b) (17.8 g,129.798 mmol) in N,N-dimethylformamide (180 mL) was addedN,N-diisopropylethylamine (67.105 g, 519.192 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI,40.299 g, 259.596 mmol) and hydroxybenzotriazole (HOBt, 39.753 g,259.596 mmol) at room temperature. The resulting reaction mixture wasstirred for 0.5 h at room temperature followed by the addition of N, Odimethyl hydroxyl amine hydrochloride (13.8 g, 141,479 mmol). Thereaction mixture was stirred at room temperature for 12 h, quenched withwater (500 mL), extracted with ethyl acetate (5×500 mL). The combinedorganic layers were dried over sodium sulfate, filtered andconcentrated. The residue obtained was purified by column chromatographyto afford N-methoxy-N,2-dimethylisonicotinamide (266c) (23 g, 98.4%yield) as a reddish thick solid; ¹H NMR (CDCl₃) δ 8.29-8.27 (d, 1H),7.08 (s, 1H), 7.02-7.01 (d, 1H), 3.27 (s, 3H), 3.07 (s, 3H), 2.32 (s,3H); MS (ES+) 181.1 (M+1).

Step-3: Preparation of 1-(2-methylpyridin-4-yl)ethanone (266d)

To a stirred solution of N-methoxy-N,2-dimethylisonicotinamide (266c)(26 g, 144.281 mmol) in THF (520 mL) was added MeLi (6.342 g, 288.562mmol, 1 M solution in THF) under nitrogen atmosphere at −78° C. Thereaction mixture was warmed to room temperature over a period of 1 h,quenched with saturated NH₄Cl solution at 0° C. The resulting reactionmixture was extracted with ethyl acetate and the organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated. The residue obtained was purified by column chromatographyto afford 1-(2-methylpyridin-4-yl)ethanone (266d) (11 g, 56.4% yield) asa reddish thick liquid; ¹H NMR (CDCl₃) δ 8.61-8.59 (d, 1H), 7.51-7.45(d, 1H), 7.45-7.44 (m, 1H), 2.56 (s, 3H), 2.53 (s, 3H); MS (ES+) 136.1(M+1).

Step-4: Preparation of3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (266e)

To a solution of 1-(2-methylpyridin-4-yl)ethanone (266d) (11 g, 81.383mmol) in methanol (110 mL) at 0° C. was added cyclopropanecarboxaldehyde (10.039 g, 143.234 mmol), aqueous potassium hydroxide(1N, 0.911 g, 16.276 mmol) and stirred at room temperature for 12 h. Thereaction mixture was cooled to 0° C., added 1N Hydrochloric acid (20.5mL) and concentrated to remove methanol. The obtained residue waspartitioned with ethyl acetate and water (75:75 mL). Aqueous layer wasseparated and extracted with ethyl acetate (2×75 mL). The combinedorganic layer were washed with water (100 mL), brine (100 mL), driedover sodium sulfate, filtered and concentrated. The residue obtained waspurified by column chromatography to afford3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (266e) (4.5 g,29.5% yield) as a reddish liquid; MS (ES+) 188.1 (M+1).

Step-5: Preparation of3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (266f)

Compound 266f was prepared from 3-cyclopropyl-1-pyridin-4-yl-propenone(266e) (8 g, 42.726 mmol) according to the procedure reported in step-2of scheme 212 as described for preparation of compound 212c gave afterpurification by column chromatography3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (266f) (5.5 g 68.1%yield) as yellow liquid; ¹H NMR (CDCl₃) δ 8.61-8.59 (d, 1H), 7.53 (s,1H), 7.47-7.46 (dd, 1H), 3.02-2.97 (m, 2H), 2.58 (s, 3H), 1.60-1.53 (m,2H), 0.71-0.66 (m, 1H), 0.41-0.37 (m, 2H), 0.05-0.01 (m, 2H); MS (ES+)190.2 (M+1).

Step-6: Preparation of(R)—N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(266g)

Compound 266g was prepared from3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (266f) (5.5 g, 29.062mmol) and R-2-methyl propane-2-sulfinamide (4.209g, 34.729 mmol)according to the procedure reported in step-1 of scheme 208 as describedfor preparation of compound 208a gave after purification by columnchromatography(R)—N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(266g) (7 g, 82.44% yield) as a yellow liquid; ¹H (CDCl₃) δ 8.51-8.49(d, 1H), 7.51-7.33 (m, 2H), 3.35-3.05 (m, 2H), 2.54 (s, 3H), 1.54-1.49(m, 2H), 1.24 (s, 9H), 0.75-0.61 (m, 1H), 0.41-0.31 (m, 2H), 0.05-0.01(m, 2H); MS (ES+) 293.2 (M+1).

Step-7: Preparation of(R)—N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(266h)

Compound 266h was prepared from(R)—N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(266g) (5.5 g, 29.062 mmol) and R-2-methyl propane-2-sulfinamide (2 g,6.839 mmol) and freshly prepared(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c)(19.10 mL, 15.28 mmol) according to the procedure reported in step-2 ofscheme 208 as described for preparation of compound 208b gave afterpurification by column chromatography(R)—N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(266h) (0.8 g, 29.0% yield) as a reddish thick liquid; ¹H NMR (DMSO-d₆)δ 8.36-8.34 (d, 1H), 7.24 (s, 1H), 7.12-7.10 (d, 1H), 6.95-6.91 (m, 1H),6.76-6.72 (m, 1H), 6.59-6.50 (m, 1H), 5.38-5.32 (m, 1H), 5.11 (s, 2H),2.49 (s, 3H), 2.05-2.01 (m, 2H), 1.55-1.51 (m, 2H), 1.16 (s, 9H),0.9-0.85 (m, 1H), 0.39-0.37 (m, 2H), 0.03-0.09 (m, 2H); MS (ES+) 404.3(M+1).

Step-8: Preparation of tert-butyl3-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(266i)

Compound 266i was prepared from(R)—N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(266h) (0.5 g, 1.238 mmol) and1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (10d) (0.573 g, 1.2 mmol) according to the procedure reported instep-3 of scheme 208 as described for preparation of compound 208c gaveafter purification by column chromatography of tert-butyl3-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(266i) (0.25 g, 26.2% yield) as a reddish thick liquid; ¹H NMR (DMSO-d₆)δ 10.66 (s, 1H), 8.42-8.40 (d, 1H), 7.65-7.49 (m, 2H), 7.48-7.28 (m,8H), 7.14 (s, 1H), 5.54 (s, 1H), 4.27-4.25 (d, 2H), 2.58 (s, 3H),1.47-1.45 (m, 2H), 1.5 (s, 9H), 1.34-1.31 (m, 2H) 1.2 (s, 9H), 0.85-0.71(m, 1H), 0.45-0.35 (m, 2H), 0.03-0.01 (m, 2H); MS (ES+) 771.4 (M+1).

Step-9: Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(266j)

To a stirred solution of tert-butyl3-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate(266i) (0.25 g, 0.324 mmol) in ethanol (5 mL) was added HCl (4N in MeOH,20 mL) at room temperature. The resulting reaction mixture was heated toreflux for 1 hour, cooled to room temperature and concentrated invacuum. The residue obtained was purified twice by flash chromatography(silica, 12g, eluting with 0-100% CMA80 in CHCl₃) to(+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(266j) (65 mg, 35.5% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.53 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.57 (m, 2H), 7.50 (m,1H), 7.42 (m, 2H), 7.29 (m, 3H), 7.19 (d, J=9.6 Hz, 1H), 7.12 (d, J=6.6Hz, 1H), 3.77 (s, 2H), 2.40 (s, 3H), 2.31-2.08 (m, 4H), 1.09-0.78 (m,2H), 0.70-0.52 (m, 1H), 0.40-0.27 (m, 2H), 0.03-−0.14 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −60.73, −124.10; MS (ES+) 567.3 (M+1); 565.3 (M−1);Optical Rotation [α]_(D)=(+) 12.38 [0.21, MeOH]. To a solution of freebase of compound (266j) (50 mg, 0.088 mmol) in MeOH (3 mL) was added HCl(3N in MeOH) (0.588 mL, 1.765 mmol), stirred for 3 h at room temperatureand concentrated in vacuum to dryness. The residue was taken up withwater/ACN freeze dried to give(+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(266j) (56 mg, 94% yield) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.78 (s, 3H), 8.77 (d, J=5.9 Hz,1H), 8.52 (s, 3H), 7.83-7.77 (m, 1H), 7.74 (m, 2H), 7.71-7.58 (m, 3H),7.58-7.47 (m, 2H), 7.40 (dd, J=7.0, 1.5 Hz, 2H), 4.11 (d, J=5.8 Hz, 2H),2.65 (s, 3H), 2.63-2.50 (m, 2H), 1.32-0.94 (m, 2H), 0.67 (m, 1H),0.48-0.24 (m, 2H), 0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.82,−119.73. MS (ES+) 567.3 (M+1), (ES−) 565.4 (M−1).

Preparation of(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(267c) Step-1: Preparation of1-(3-(N-(tert-butoxycarbonyl)carbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (267a)

To a solution of1-(3-carbamimidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (236g) (1.2 g, 4.02 mmol) in MeOH—H₂O (50 mL, Ratio: 1:2) was added(Boc)₂₀ (1.121 g, 4.83 mmol) and sodium hydroxide (0.322 g, 8.05 mmol).The resulting mixture was stirred at room temperature for 12 h.Additional (Boc)₂₀ (0.878 g, 4.02 mmol) was added and the resultingmixture was stirred for 8 h, diluted with water (100 mL) and extractedwith ethyl acetate (3×100 mL). The organic layers were combined, dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 40 g, elutingwith 0-100% CMA-80 in chloroform) to afford1-(3-(N-(tert-butoxycarbonyl)carbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (267a) (205 mg, 0.515 mmol, 12.79% yield) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.12-7.94 (m, 2H), 7.77-7.65 (m, 1H),7.57 (t, J=7.8 Hz, 1H), 7.13 (s, 1H), 1.45 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −60.45; MS (ES+): 399.4 (M+1), (ES−) 397.3 (M−1).

Step-2: Preparation of tert-butyl(3-(5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(267b)

To a solution of1-(3-(N-(tert-butoxycarbonyl)carbamimidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (267a) (150 mg, 0.377 mmol) in THF (20 mL) at 0° C. was added NMO(44.1 mg, 0.377 mmol), isobutylchloroformate (153 mg, 1.125 mmol) andstirred at 0° C. for 1 h. To the reaction mixture was added(R)—N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(214e) (156 mg, 0.377 mmol), lithium chloride (23.95 mg, 0.565 mmol),stirred at 0° C. for 2 h, quenched with water (10 mL) and extracted withethyl acetate (3×20 mL). The organic layers were combined, dried,filtered, and concentrated in vacuum to dryness. The residue obtainedwas purified by flash column chromatography (silica gel 12g, elutingwith 0-100% EtOAc in hexane) to tert-butyl(3-(5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(267b) (88 mg, 0.111 mmol, 29.4% yield) as a white solid; ¹H NMR (300MHz, Chloroform-d) δ 8.09 (m, 1H), 7.90 (s, 1H), 7.85 (d, J=8.5 Hz, 1H),7.67-7.61 (m, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.47 (m, 1H), 7.39 (d, J=8.2Hz, 2H), 7.20 (m, 1H), 7.04 (m, 1H), 6.99-6.92 (m, 1H), 2.58 (m, 2H),1.49 (s, 9H), 1.19 (s, 9H), 0.97-0.85 (m, 2H), 0.59 (m, 1H), 0.36 (m,2H), −0.12 (m, 2H); MS (ES+): 794.6 (M+1); IR (KBr) 2232 cm⁻¹.

Step-3: Preparation of(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(267c)

To a solution of to tert-butyl(3-(5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate(267b) (70 mg, 0.088 mmol) in EtOH (10 mL) was added HCl (4N in dioxane)(0.220 mL, 0.882 mmol) and heated at reflux for 10 min. The solution wasconcentrated under vacuum to dryness and the residue obtained waspurified by flash column chromatography (silica gel, eluting with 0-100%CMA80 in chloroform) to furnish compound 267c (17 mg, 0.029 mmol) freebase as a white solid. The free base was converted into HCl salt byusing HCl (4N in dioxane, 0.1 mL) and freeze dried to afford(−)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(267c), 17 mg, 0.027 mmol, 30.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.26 (s, 3H), 8.16 (s, 1H), 8.04-7.98 (m,2H), 7.89 (dt, J=7.3, 1.4 Hz, 1H), 7.83 (s, 1H), 7.71-7.54 (m, 7H), 7.42(dd, J=10.1, 8.8 Hz, 1H), 7.29-7.19 (m, 1H), 2.50 (dp, J=39.9, 1.8 Hz,2H), 1.06 (tt, J=12.3, 5.3 Hz, 2H), 0.77-0.59 (m, 1H), 0.48-0.29 (m,1H), −0.02 (s, 2H); ¹⁹F NMR (282 MHz, MeOH-d₄) δ −64.55, −128.38; MS(ES+) 613.5 (M+Na); IR (KBr) 2235 cm⁻¹; Analysis calculated forC₃₁H₂₆F₄N₆O₂.HCl.2.75H₂O; C, 55.03; H, 4.84; N, 12.42; Found: C, 55.30;H, 4.81; N, 12.00; Optical rotation: [α]_(D)=(−) 3.2 [0.125, MeOH].

Preparation of(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(268g) Step-1: Preparation of ethyl1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268b)

To a solution of2-(2,4-dimethoxybenzyl)-7-hydrazinylisoquinolin-1(2H)-iminehydrochloride (235e) (13.434 g, 41.4 mmol) in ethanol (50 mL) was addedthe copper complex (268a) (prepared according to Russian ChemicalBulletin, 1990, 1273-1277) (10.79 g, 41.4 mmol). The resulting mixturewas cooled to 0° C., added conc. HCl (15.10 g, 414 mmol) and stirred atroom temperature overnight. Additional HCl (7.02 g, 193 mmol) was addedand reaction mixture was heated at reflux overnight, cooled to roomtemperature and concentrated in vacuum. The residue was purified byflash column chromatography (silica gel, eluting with CMA80 inchloroform 0-70%) to afford ethyl1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268c) (1.90 g, 5.42 mmol, 13.10% yield) and ethyl1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268b) (4.1 g, 8.19 mmol, 19.78% yield). ¹H NMR (300 MHz, DMSO-d₆) δ8.45 (s, 1H), 7.76-7.55 (m, 3H), 7.27 (d, J=7.4 Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.48 (dd, J=8.4, 2.3 Hz, 1H), 6.21 (d,J=7.4 Hz, 1H), 4.97 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.74(s, 3H), 1.32 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO) δ −56.85.

Step-2: Preparation of ethyl1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268c)

Compound 268c was prepared from ethyl1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268b) (4.1 g, 8.19 mmol) according to the procedure reported for thepreparation of compound 253a, step-1 scheme-253 gave after purificationby column chromatography (silica gel, eluting with CMA80 in chloroform0-40%) ethyl1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268c) (2.4 g, 6.85 mmol, 84% yield) as an off white solid; ¹H NMR (300MHz, Chloroform-d) δ 8.49 (s, 1H), 7.86 (q, J=8.6 Hz, 2H), 7.52 (d,J=6.5 Hz, 1H), 7.36 (s, 1H), 7.02 (d, J=6.1 Hz, 1H), 4.38 (q, J=7.0 Hz,2H), 1.34 (t, J=7.0 Hz, 3H).

Step-3: Preparation of ethyl1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268d)

To a solution of ethyl1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268c) (1.90 g, 5.42 mmol) in acetonitrile (75 mL) was added DIPEA (4.74mL, 27.1 mmol), Boc anhydride (3.55 g, 16.27 mmol), DMAP (0.066 g, 0.542mmol) and stirred at room temperature overnight. Additional Bocanhydride (2.368 g, 10.85 mmol) were added, and the reaction mixture washeated at 60° C. for 4 h. The reaction mixture was cooled to roomtemperature, added Boc anhydride (1.776 g, 8.14 mmol) and heated at 50°C. overnight. The reaction mixture was evaporated to dryness, treatedwith brine (100 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organics were dried over MgSO₄, filtered, evaporated to drynessand the residue obtained was purified by flash column chromatography(silica gel 40 g, eluting with 0-40% ethyl acetate in hexane) to affordethyl1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268d) (647 mg, 1.175 mmol, 21.67% yield) as a white semi-solid. ¹H NMR(300 MHz, Chloroform-d) δ 8.57 (d, J=5.7 Hz, 1H), 8.16 (s, 1H), 8.05 (d,J=8.8 Hz, 1H), 7.87 (dd, J=8.8, 2.0 Hz, 1H), 7.78 (d, J=5.7 Hz, 1H),7.42 (s, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H), 1.32 (s,18H).

Step-4: Preparation of1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicAcid (268e)

To a solution of ethyl1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(268d) (544 mg, 0.988 mmol) in THF/H₂O (30 mL, Ratio: 3:1) at roomtemperature was added lithium hydroxide monohydrate (415 mg, 9.88 mmol)and heated at 67° C. overnight. The reaction mixture was diluted withEtOAc (35 mL), organic layer was separated and the aqueous layer wasacidified with conc. HCl to pH 2. The white precipitate obtained wascollected by filtration, washed with water (2×5 mL), dried in vacuum tofurnish1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (268e) (295 mg, 93%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (s, 1H), 7.98-7.86 (m, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.61 (s, 1H),7.25 (s, 2H), 7.06 (d, J=5.7 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO) δ −56.71;MS (ES+) 323 (M+1), (ES−) 321 (M−1).

Step-5: Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(2368f)

Compound 268f was prepared from1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (268e) (100 mg, 0.310 mmol) and(R)—N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(216b) (121 mg, 0.310 mmol) using procedure reported in step-3 ofscheme-208 to furnish after purification by column chromatography(silica gel, eluting with 0-40% CMA80 in CHCl₃)1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(268f) (120 mgs) which was used as such without further purification.

Step-6:(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(268g)

To a solution of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(268f) (120 mg, 0.173 mmol) in ethanol (10 mL) was added HCl (32 mg,0.865 mmol) and heated at reflux for 3 h. The reaction mixture wascooled to room temperature, concentrated in vacuum and purified by flashcolumn chromatography (silica gel, eluting with chloroform in CMA800-40%) to give(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(268g) (7 mg, 0.012 mmol, 6.86% yield) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.54 (d, J=2.3 Hz, 1H), 8.49-8.41 (m,2H), 7.96-7.89 (m, 2H), 7.86-7.76 (m, 1H), 7.68 (s, 1H), 7.63 (dd,J=7.5, 2.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.32 (m, 1H), 7.19 (dd, J=10.2,8.6 Hz, 1H), 7.03 (d, J=5.1 Hz, 3H), 2.34 (s, 2H), 2.23 (m, 2H), 1.06(m, 2H), 0.64 (m, 1H), 0.44-0.31 (m, 2H), −0.01-−0.15 (m, 2H); ¹⁹F NMR(282 MHz, DMSO) δ −56.82, −124.34; MS (ES+) 590.3 (M+1); (ES−) 588.3(M−1); Optical rotation: [α]_(D)=(+) 10.67 [0.225, MeOH].

Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269b) Step-1: Preparation of1-(1-bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269a)

Compound 269a was prepared from1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrimidine-2,4(1H,3H)-dione(263b) (163 mg, 0.537 mmol) and1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (253c) (337 mg, 0.645 mmol) according to the procedure reported instep-3 of scheme 208 for preparation of compound 208c to afford afterpurification by flash column chromatography [silica gel 40 g, elutingwith 0-90% EtOAc/MeOH (9:1, v/v) in hexane]1-(1-bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269a) (55 mg, 0.068 mmol, 12.7% yield) as a white solid; MS (ES+),830.4 (M+Na); (ES−) 806.4 (M−1).

Step-2: Preparation of1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269b)

To a solution of1-(1-bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269a) (55 mg, 0.068 mmol) in MeOH (15 mL) was added HCl (3N in MeOH)(0.45 mL, 1.36 mmol) and stirred at room temperature overnight. Thereaction was concentrated in vacuum and the residue obtained waspurified by flash column chromatography (silica gel 24 g, eluting with0-40% CMA80 in CHCl₃) to furnish1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(269b) (9.0 mg, 0.015 mmol, 41.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.36 (s, 1H), 10.60 (s, 1H), 8.42 (s, 1H), 7.88 (d,J=5.7 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.74-7.63 (m, 3H), 7.52 (d, J=7.2Hz, 1H), 7.29 (d, J=7.9 Hz, 2H), 6.98 (m, 3H), 5.57 (m, 2H), 2.31-1.98(m, 2H), 1.32-0.95 (m, 2H), 0.78-0.57 (m, 1H), 0.47-0.29 (m, 2H),0.13-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −60.73, −121.27.

Preparation of(−)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-((ethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(270a)

To a solution of(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(42b) (0.25 g, 0.46 mmol) in MeOH (10 mL) was added acetaldehyde (0.16mL, 2.8 mmol) and stirred at room temperature for 10 mins. To thereaction mixture was added sodium borohydride (0.035 g, 0.93 mmol) andcontinued stirring at room temperature for 6 h. The reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (2×40 ml).The combined organics were washed with brine, dried (MgSO₄), filteredand concentrated in vacuum. The residue obtained was purified by flashchromatography [silica gel 24 g, eluting with 0 to 30% CMA80 inchloroform) to afford compound 270a (0.11 g, 0.194 mmol, 41.8% yield)free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.53 (s, 1H),7.63 (d, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.50-7.24 (m, 9H), 7.22-7.14 (m,2H), 4.83 (s, 1H), 3.73 (s, 2H), 2.45 (m, 2H), 2.26 (d, J=6.6 Hz, 2H),0.96 (m, 4H), 0.43-0.30 (m, 2H), 0.04 (m, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −60.54, −123.79; MS (ES+) 566.4 (M+1); MS (ES−) 564.4 (M−1),600.3 (M+Cl); The free base (0.7 g) was converted to HCl salt using 3NHCl (5 eq) to obtain(−)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-((ethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(270a) hydrochloride as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.81(s, 1H), 10.16 (s, 2H), 9.20 (s, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.80-7.11(m, 12H), 5.75-5.57 (m, 1H), 4.21 (t, J=5.8 Hz, 2H), 3.05-2.83 (m, 2H),2.70 (m, 2H), 1.18 (m, 4H), 0.60-0.50 (m, 2H), 0.29 (m, 2H); Opticalrotation: [α]_(D)=(−) 3.57 [0.28, MeOH].

Example 271

Plasma Kallikrein Activity Assay.

The effect of compounds of the invention on human plasma kallikreinactivity was determined using the chromogenic substrates (DiaPharmaGroup, Inc., West Chester, Ohio, USA). In these experiments, 2 nMkallikrein (Enzyme Research Laboratories, South Bend, Ind., USA) wasincubated with 80 μM S2302 (H-D-Pro-Phe-Arg-p-nitroaniline) in theabsence or presence of increasing concentrations of compounds of theinvention in a final volume of 200 μL Tris-HCl buffer (200 mM NaCl; 2.5mM CaCl₂; 50 mM Tris-HCl, pH 7.8).

After incubation at 30° C., the activity of kallikrein was measured as achange in absorbance at OD 405 nm using BioTek PowerWave X340 MicroplateReader (Winooski, Vt., USA). Data were analyzed using SigmaPlot software(Systat Software, Inc., San Jose, Calif., USA) (Four Parameter LogisticCurve). Ki values for the inhibitors were determined using theCheng-Prusoff equation (Biochem. Pharmacol. 1973, 22, 3099).

The compounds disclosed in this application have Ki values less than 1micromolar (μM) for the plasma kallikrein enzyme. See Table 1.

TABLE 1 Measured Ki values for compounds. Com- Com- Com- pound Ki (nM)pound Ki (nM) pound Ki (nM) 161e >100  28f >100  77e 0.1-50 162c >100 29e 0.1-50  43f 0.1-50 163g >100  30g >100  44c 0.1-50  17d >100 31f >100  78d 0.1-50  18f >100  32f  >50-100  79f 0.1-50  19d >100 33e >100  80h 0.1-50  20d >100  33f >100  87f 0.1-50  18g  >50-100 34d >100  88b 0.1-50  22b >100  35g  >50-100  82f 0.1-50  23c >100  34c0.1-50  83c 0.1-50  24c >100  18e >100  46g 0.1-50  25b  >50-100 81c >100 205f >100  25c >100  39e >100  89g 0.1-50  26f >100  40b >100 91a 0.1-50  18i  >50-100  41e 0.1-50  86g 0.1-50  18h  >50-100  74a0.1-50  45g 0.1-50  21e >100  75a  >50-100  47f 0.1-50  18j >100  38d0.1-50  92g 0.1-50  18k 0.1-50  76h >100  84h 0.1-50  27f  >50-100  36d0.1-50  85c 0.1-50  93b >100 109f 0.1-50 128g 0.1-50  94b 0.1-50 110f0.1-50 129f 0.1-50  95i 0.1-50 111f 0.1-50 130g 0.1-50  96f 0.1-50 112g0.1-50 131b 0.1-50  48f 0.1-50 113f 0.1-50 132f 0.1-50 164e 0.1-50 114f0.1-50 133g 0.1-50  97f >100 115e  >50-100 134f 0.1-50  98b 0.1-50 116e0.1-50 135c 0.1-50  99g 0.1-50 117e 0.1-50 136a >100 100e 0.1-50 118f0.1-50 137a 0.1-50 101e 0.1-50 119e 0.1-50 137b >100 102b 0.1-50 120e0.1-50 138f 0.1-50 103b 0.1-50 122g 0.1-50  52h 0.1-50 104f 0.1-50 121f0.1-50 139b 0.1-50 105g 0.1-50 123g 0.1-50 140e 0.1-50  49h 0.1-50 124f0.1-50 167f >100 106a 0.1-50  51f 0.1-50 141e 0.1-50  50f 0.1-50 125g0.1-50 142f 0.1-50 107f 0.1-50 126g 0.1-50 1431 0.1-50 108e 0.1-50 127f0.1-50 144d 0.1-50 145c >100  57e 0.1-50 181b >100 146g 0.1-50  60e0.1-50 182b >100 147e 0.1-50  71a 0.1-50 183b >100 148b 0.1-50  71b0.1-50 184b >100 149b 0.1-50  65a 0.1-50 185b >100  53f 0.1-50  65b0.1-50 186b >100 150f 0.1-50 192f 0.1-50 187b >100 153b 0.1-50 168b0.1-50 188b 0.1-50 151g 0.1-50 169b >100 189b >100 152d 0.1-50 170b >100190b >100 154e 0.1-50 171b >100 193f 0.1-50 155c 0.1-50 172b >100191b >100 156c 0.1-50 173b >100 195f 0.1-50  54e 0.1-50 174b >100 196f0.1-50  55b 0.1-50 175b >100 197f 0.1-50  58c 0.1-50 176b >100 198f0.1-50  56c 0.1-50 177b >100 194f 0.1-50  68c 0.1-50 178b >100 199f0.1-50  61e 0.1-50 179b >100 200f 0.1-50  59c 0.1-50 180b >100 201f0.1-50 202f 0.1-50 166e 0.1-50  42b 0.1-50 203f >100 165e 0.1-50  42a0.1-50 157a >100  50g 0.1-50  67a 0.1-50 158a >100  50h 0.1-50  67b0.1-50 159a >100  43g 0.1-50  70a 0.1-50 160a >100  43h 0.1-50  70b0.1-50 207j 0.1-50  44d 0.1-50  69a 0.1-50 247c 0.1-50  44e 0.1-50  69b0.1-50 247e 0.1-50  47g 0.1-50  68d 0.1-50 248j 0.1-50  47h 0.1-50  68e0.1-50 249b 0.1-50  46h 0.1-50  63a 0.1-50 250c 0.1-50  46i 0.1-50  63b0.1-50 252c 0.1-50  48g 0.1-50  73a 0.1-50 251e  >50-100  48h 0.1-50 73b 0.1-50 260b 0.1-50  51g 0.1-50  72c 0.1-50 262f 0.1-50  51h 0.1-50 72d 0.1-50 263d 0.1-50  64a 0.1-50  66a 0.1-50  15g >100  64b 0.1-50 66b 0.1-50  16b >100  49i 0.1-50  37b 0.1-50  90f >100  49j 0.1-50  37a0.1-50 206d 0.1-50 231d 0.1-50 244g 0.1-50 205d 0.1-50 232a >100 244h0.1-50 205e 0.1-50 246f 0.1-50 244i 0.1-50 208d 0.1-50 234d >100 244j0.1-50 209d 0.1-50 235g 0.1-50 244k 0.1-50 210d 0.1-50 218c 0.1-50 253e0.1-50 211d 0.1-50 219c 0.1-50 245c 0.1-50 212g 0.1-50 239d >100 257b0.1-50 214g 0.1-50 267c >100 254c 0.1-50 213d 0.1-50 240b 0.1-50 255a0.1-50 222k >100 236h 0.1-50 265d 0.1-50 223f >100 237a 0.1-50 256a0.1-50 220f 0.1-50 238c 0.1-50 268g  >50-100 224b >100 241a 0.1-50 258g0.1-50 225a 0.1-50 215d >100 248l 0.1-50 226a >100 238d 0.1-50 248k0.1-50 227d 0.1-50 221i 0.1-50 264g 0.1-50 228a 0.1-50 216d 0.1-50 261k0.1-50 229i 0.1-50 243a 0.1-50 259d 0.1-50 230a >100 217d  >50-100 266j0.1-50 269b 0.1-50 270a  >50-100

EQUIVALENTS

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

1-146. (canceled)
 147. A compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:


148. The compound of claim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 149. The compound ofclaim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 150. The compound ofclaim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 151. The compound ofclaim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 152. The compound ofclaim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 153. The compound ofclaim 147, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 154. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:


155. The compound of claim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 156. The compound ofclaim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 157. The compound ofclaim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 158. The compound ofclaim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 159. The compound ofclaim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 160. The compound ofclaim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 161. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:


162. The compound of claim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 163. The compound ofclaim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 164. The compound ofclaim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 165. The compound ofclaim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 166. The compound ofclaim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 167. The compound ofclaim 161, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 168. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:


169. The compound of claim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 170. The compound ofclaim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 171. The compound ofclaim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 172. The compound ofclaim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 173. The compound ofclaim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 174. The compound ofclaim 168, wherein the compound is

or a pharmaceutically acceptable salt thereof.